HAVCR2 expression

The combination of immunotherapy and SABR changed the immunophenotype of blood T cells, with some shifts attributable to SABR. Importantly, we identified a T-cell signature at baseline that best predicted response. Validation of these findings in an independent cohort could confirm these as biomarkers at baseline or early during treatment, and whether these can be utilised to stratify patients for high or low intensity treatment to reduce toxicity.

Our study unveils a novel mechanism underlying NK cell exhaustion/dysfunction in the EC microenvironment. MLLT1 could be a potential target in future NK cell-mediated immunotherapy against EC.

Moreover, expression data analyses showed a positive correlation between the levels of Gal-9 and PD-L1 in cancer patients. Conclusion Our data revealed an unexpected link between the Gal-9/TIM-3 and PD-L1/PD-1 axes in the TME, suggesting Gal-9 as a potential predictive biomarker and therapeutic target in cancer immunotherapy.

Moreover, immune infiltration analysis showed that ABCC4 expression had a significantly positive correlation with NK infiltration as well as immunotherapy target TIM-3 (HAVCR2) expression. Collectively, our findings indicated that ABCC4 might be a predictive biomarker of selinexor sensitivity in MM patients, which could be enhanced if combined with immunotherapy drugs such as TIM-3 inhibitor.

Decreased MEG3 expression could be considered an alarm signal in the transition from a premalignant cervical lesion to invasive cancer, while altered expression levels of TIMP3, SOX1, MLH1, MALAT1 and miR-205-5p could serve as early biomarkers in the diagnosis of premalignant cervical lesions. Future studies, including a larger number of patients with CIN, will be of particular importance in validating these observations.

In summary, this study showed that after ex vivo expansion for 15 days, CD8PD-1 T cells could be identified as tumor-reactive cells in patients treated for GC. Changing TCR species can predict the extent of CD3CD8PD1 T-cell growth and the effect of ACT treatment.

We demonstrate that, far from being histo-pathologically monotonous, DLBCL has a complex tumor architecture, and that changes in tumor topology can be correlated with clinically relevant features. This analysis identifies candidate biomarkers and therapeutic targets such as TIM-3, CCR4, and CXCR3 that are relevant for combination treatment strategies in immuno-oncology and cellular therapies.

We propose a novel perspective that KMT1A involves in the growth and metastases via the TIMP3/PI3K/AKT axis in CC. In summary, our study identified a vital role played by KMT1A in the development of CC and the epigenetic mechanism, indicating that targeting KMT1A-related pathways could be conducive to the therapies for CC.

Our findings prove the potential of dendrimer-based platforms for therapeutic applications, which might help to eradicate the population of cancer cells with augmented chemotherapy resistance. Moreover, the results further promote our functional stem cell technology as suitable component in early stage drug development.

Our murine HNSCC model demonstrates efficacy of PD-1 blockade during chemoradiotherapy. However, while PD-1-expressing T cells decreased with this therapy, human PBMC findings also identified an increase in populations contributing to immune exhaustion. These findings further characterize PD-1 blockade during chemoradiotherapy for HNSCC and highlight potential competing mechanisms of immune evasion.

Altogether, DFB dampens CCL2 and preserves progenitor Tex in obese microenvironment to restrain CRC progression. These finds provide unambiguous evidence that traditional Chinese formula DFB can prevent tumor progression by modulating adaptive immunity and give rise to strong rationale for further clinical verification.

Our results strongly support the potential clinical use of pracinostat as a novel therapy for human glioma in the near future.

No abstract available

The results of flow cytometry showed that the expression of antigen KI-67 (ki67) and IFN-γ in tumor infiltrating T cells significantly increased, while the expression of PD-1 and TIM-3 in immune checkpoints decreased significantly. Conclusion M-SNPs can mediate the specific targeted delivery of PD-1 siRNA to homologous tumor tissues, activate anti-tumor immune response and inhibit tumor growth, which may be a potential therapeutic strategy for oral cancer.

Thus, the TIM-3/galectin-9 signalling pathway may impact anticancer immune reactions in the tumour microenvironment of patients with TNBC. Further investigation will be necessary to determine the molecular mechanisms underlying these relationships.

Furthermore, VISTA and B7H3 are prognostic biomarkers in advanced PTC. Single or combined blockade targeting these ICPs might be effective for advanced TCs in the future.

We suppose, that dendrimer-based approach can be useful and perspective tool for delivery of therapeuthic microRNAs into tumor cells. At the same moment, characterization of their effects on interactions between tumor and immune microenvironment demands the further studies.

Conclusion Oral-AZA Tx was significantly associated with LTS vs PBO. In univariate analysis, Int-risk cytogenetics and NPM1 mut at Dx, and MRD response on-study, were significantly prognostic of LTS in both arms, whereas MRD– status at BL (post-IC) was associated with LTS only in the PBO arm.

(2021) showed that microRNAs in malignant T cells could regulate the expression of PD-1, CTLA4, TIM3, and LAG3 and simultaneously mediate evasion from immune surveillance. These findings get us one step closer in our further investigation of whether those molecules could be targeted therapeutically.

Overall, the current study suggested that TIM-3 and OX40 are frequently expressed intratumoral immune receptors in HGSOC and thus represent promising immune targets. Furthermore, the present analysis strongly suggested that OX40 was significantly associated with a longer survival and could potentially be utilized as a prognostic factor for improved patient outcomes in HGSOC.

Our findings suggest that in ovarian cancer, immunosuppressive TIGIT+M2 TAMs can be redirected into a more cytotoxic effector population. Therefore, the blockade of TIGIT should be evaluated as novel therapeutic treatment option for ovarian cancer patients.

Similar to our results, TCGA data showed that patients with CBF translocations had significantly higher mRNA expression level of HAVCR2 (the gene encoding TIM-3) (median, 9.81 versus 8.69, p<0.0001), and as all patients in the cohort were divided into two groups based on the median HAVCR2 expression level, 5-year overall survivals were not significantly different (low versus high, 24.95% versus 24.54%, p=0.6660). TIM-3 expression level on AML blasts correlates with presence of CBF translocations rather than clinical outcomes.

In addition, the results of quantitative real-time PCR and immunohistochemistry analysis demonstrated the abnormal expression of TIMP3 and ATG9A in actinic keratosis and cutaneous squamous cell carcinoma skin tissues. These findings suggest the protective effects of trehalose in normal keratinocytes and its inhibitory effects on cancerous keratinocytes, possibly mediated by activation of autophagy and regulation of TIMP3 and ATG9A, providing the mechanistic basis for the potential use of trehalose in the prevention or treatment of UVB-induced skin diseases.

Our data demonstrated strong correlations between FoxP3Helios Tregs but not FoxP3Helios non-Tregs and multiple immune checkpoints, especially in the TME, providing a rationale for targeting these cells with highly immunosuppressive characteristics. Understanding the correlations between different immune checkpoints and Treg/T cell subsets in cancer patients could improve our knowledge of the underlying mechanisms of Treg-mediated immunosuppression in cancer.

Conclusions We have identified a chimeric Fas-CD40 protein that is able to not only rescue FasL-mediated T-cell apoptosis, but also elicit superior proliferation and anti-tumour cytotoxicity in the presence of FasL. Figure Legend PBMCs expressing CAR alone or with Fas-TNFRs were cultured with immobilised FasL for five days, at which point cell count was analysed by flow cytometry.

The expression of TIMP3 in KIRC tissues was also verified by immunohistochemistry, and the results were consistent with our analytical data. In summary, this study constructed a new model with clinical predictive value and identified the WDFY3-AS2/TIMP3 pathway that was closely associated with the prognosis of KIRC, which could serve as a promising biomarker for the diagnosis and treatment of KIRC.

Therefore, it was concluded that TCF1Tex was the major CD8PD1Tex subset in the HNSCC TIME and that these cells favor patient survival. A high proportion of TCF1Tex was associated with greater Treg abundance.

Early phase clinical trials with different anti-TIM-3 monoclonal antibodies have shown a safe toxicity profile, as cobolimab, LY3321367, or sabatolimab; however, the general antitumor activity remains to be determined and further investigations are needed. However, the TIM-3 pathway is highly complex in terms of non-canonical signaling, broad expression by different immune cells and multiple ligands. Different anti-TIM-3 inhibitors are currently on research, either as monotherapy or in combination with other immunotherapies or chemotherapy, aiming to overcome resistance.

In conclusion, the Vδ1 T cell population showed a high prevalence in the MALs and primary tumors of OvCA patients. Due to their (co-)expression of targetable immune receptors, in particular TIGIT with PD-1 and CD39 in TILs, Vδ1 T cell-based approaches combined with the inhibition of these targets might represent a promising strategy for OvCA.

Our findings uncover the pleiotropic effects of 1α,25(OH)D in rescuing the exhausted phenotype of human cytotoxic T cells in patients with tumor and in promoting their antitumor immunity.

CaboNivo was clinically active, well-tolerated, and favorably modulated peripheral blood immune subsets in mUC patients refractory to CPI.

In this mini-review, we investigate the function of dendritic cells and T cells based on Flt3-ITD mutation and immune evasion as a result of this abnormality. Finally, we discuss some AML therapeutic strategies, including targeting Flt3 on DCs and TIM-3 on T cells as immune receptors to treat this hematopoietic malignancy.

Conclusions : The significance of TIM-3 among immune co-inhibitory receptors that could be expressed in the tumor microenvironment of TGCT was demonstrated for the first time. We showed that there is a need to pay attention to TIM-3 expression for the treatment of TGCT.

At the same time, in B16-OVA tumor model, transferred genetically edited OT-1 CD8 T cells promoted longer survival compared to control T cells and showed enhanced expansion without associated toxicity. Our study supports the notion that antigen-specific adoptive T cell therapy with concomitant genetic disruption of multiple checkpoint inhibitory receptors could represent an effective antitumor immunotherapy approach with improved tolerability profile.

TIM-3 is highly expressed in EOC tissue to promote malignant behaviors of the tumor cells possibly by activating the Wnt/β-catenin signal pathway.

These data suggest that altering the expression of TIM-3+ on T reg has the potential to act as an effective target to alter tumor microenvironment. Targeting TIM-3+ T reg may therefore be attractive model to study, along with other combination immunotherapy to increase the success in immunotherapy on patients who develop resistance to primary immunotherapy.

GSEA pathway enrichment analysis from RNA seq of PSGL-1 KO CD19 CAR-T cells shows PSGL-1 KO CD19-CAR-T cells has central memory phenotype and lower exhaustion profile, further confirmed by immunophenotyping these PSGL1-KO CD19-CAR-T cells. From our study, it is evident that PSGL-1 KO CAR-T cells can overcome the limitations of CAR-T cells hurdles like maintaining the central memory phenotype and lower exhaustion In summary, our study is clear evident that PSGL-1 KO CAR-T cells can be used as universal CAR-T system to target all kind tumors not limiting to hematological cancers.

Additionally, 4-1BB, an indicator of TCR engagement, trended higher in RCC (mean=8.6%, IQR=1.4-46.7%) as compared to BCa (median=1.9%, IQR=0.4-8.6%). These data highlight the heterogeneity of human TILs isolated from distinct tumor types and provide insight into the basal expression of actionable therapeutic targets.

We also found overlap of TCR profiles between DPT and CD8+ T cell subsets (Tex, ZNF683-CD8, and GZMK-CD8) in RCC. Together, multimodal single-cell analysis of TILs highlighted heterogeneity among tumor types that may provide insight into novel strategies to treat cancer.

We further observed that after tumor entry, Tcf-1+PD-1lo tumor-specific T cells progressively acquired the expression of inhibitory receptors, such as Tim-3, correlating with the phenotypes that represent tumor retention and residence. Thus, TRM exist within tumors, durable intratumoral residence was not informed by common markers associated with pathogen-specific TRM that have been described in healthy tissue, but tumor-specific T cells become resident upon tumor antigen recognition and the subsequent upregulation of CD39 and Tim-3.

Moreover, miR-650 down-regulation or TIMP3 up-regulation reversed the effects of lncRNA NBR2 knockdown that caused an enhancement of cell viability, migration and invasiveness in remifentanil-treated HCC cells. Thus remifentanil reduces the proliferation, migration and invasion of HCC cells via the lncRNA NBR2/miR-650/TIMP3 axis in vitro.

Regular physical activity was associated with improved outcomes in unresectable HCC receiving combined lenvatinib plus anti-PD-1 therapy. Physical activity may improve therapeutic efficacy by reprograming the tumor microenvironment from an immunosuppressive to immunostimulatory phenotype.

BCL-2 expression in the T cells of CLL patients is associated with immunosuppression via promotion of Treg abundance and CTL exhaustion.

TIM-3 and LAG-3 were independent biomarkers for the early diagnosis of NSCLC. The combination of TIM-3, LAG-3, and CD137 could increase the diagnostic accuracy.

Our results indicate a key role for the TIM-3 immune checkpoint in oncolytic adenoviral immunotherapy. Moreover, our results identify TIM-3 as a potential biomarker for oncolytic adenoviruses and create rationale for combination with passive immunotherapy for a subset of patients.

Survival analysis using TCGA data showed that high COL1A1 and COL4A2 expression levels correlate with poor survival in PM patients. Herein, we identified markers with the potential to improve diagnosis and prognostic stratification of biphasic PM, which is still an orphan tumor.

The decline of mRNAs was, at least partly, owing to the destabilization of these mRNAs by one of the IGF2BPs. In conclusions, the ALKBH5-IGF2BPs axis promotes cell proliferation and tumorigenicity, which in turn causes the unfavorable prognosis of NSCLC.

Moreover, some immune checkpoints displayed a more remarkable expression on the immune cells in GME. And the profile of checkpoint expression in PBMC was partially consistent with that in GME.

The results provide insights on mechanisms underlying the inadequate immune response to leukemic cells in TP53-mutated AML and open up for further exploration toward novel treatment regimens for these patients.

TIM-3 blockade increases exposure of intratumoral CD8 T cells to cDC1-derived cytokines, with implications for the design of therapeutic strategies using antibodies against TIM-3.

Our results also showed that NK cells from peripheral blood and bone marrow of MM patients expressed much higher levels of Tim-3 than their counterparts from controls. Taken together, Tim-3 may be an important target molecule used for developing an antibody and/or NK cell based immunotherapeutic strategies for MM.

The present study showed that Tim-3/Gal-9 are associated with poor prognosis in glioma patients and induce NLRC4 inflammasome formation and activation. We proposed that a Tim-3/Gal-9 blockade could be beneficial in glioma therapy as it would reduce the inflammatory microenvironment by downregulating the NLRC4 inflammasome.

These data suggest that the neuroendocrine system may modulate T-cell activity, specifically the expression of PD-1 ligand. Furthermore, sustained release of stress hormones may promote an immunosuppressive tumor microenvironment, leading to T-cell exhaustion, immune evasion, and tumor progression.

Paraffin sections of AML BM are being evaluated for NLRP3 pathway markers by immunohistochemistry. Understanding remodelling of BM-MSC, leukemia target and immune cell dynamics through NLRP3 pathway regulation in stroma microenvironment may provide crucial leads in therapeutic modulation of the immune response within the stem cell niche.

Evaluation of stromal and tumor cell immune profiling indicates that compared to other subtypes, PCa with HRD alteration have a unique immune profile abundant in CD8+ cell, and PD-L2 and A2aR expression. Not only does this indicate an immune active TME but also identifies therapeutically actionable immunotherapeutic pathways which may render clinical benefit in this patient population.

From our study, it is evident that PSGL-1 KO CAR-T cells can overcome the limitations of CAR-T cells hurdles like maintaining the memory phenotype, exhaustion and leakiness into different organs, more overPSGL-1 KO CAR-T cells can over comes VISTA dependent CAR-T cell functional inhibition. In summary, our study is clear evident that PSGL-1 KO CAR-T cells can be used as universal CAR-T system to target all kind tumors not limiting to hematological cancers.

Whether the expression and genomic status of TIM-3 and its ligands, Ceacam-1, galectin-9, HMGB1 and phosphatidyl serine (PtdSer) are associated with clinical outcome or any indication would be essential for patient selection for TIM-3 targeting therapies. Human PD-1/TIM-3 double-knock-in mice (PD-1/TIM-3 dKI HuGEMM™) engrafted with CT26.WT tumor model were used to test human PD-1 antibody (Keytruda) and TIM-3 antibody (MBG453). Evaluation in preclinical model demonstrated that TIM-3 blockade may cause NK cell proliferation to enhance anti-tumor immunity. In addition, the expression and genomic alteration of TIM-3 and its ligand have prognostic values for certain cancers.

Inhibitory receptor/ligand interactions within the tumor microenvironment can dramatically reduce T cell function, suggesting tumor cells may increase expression of the ligands for PD-1, Tim-3 and Lag-3 for protection from tumor-infiltrating lymphocytes. In a model of advanced ovarian cancer, triple checkpoint blockade significantly improved the anti-tumor function of transferred engineered T cells and improved outcomes in mice in a setting in which single checkpoint blockade had no significant activity. These results suggest that disrupting multiple inhibitory signaling pathways simultaneously, which can be more safely pursued in a cell intrinsic form through genetic engineering, may be necessary for improved efficacy in patients.

CART cells manufactured with duvelisib (Duv-CART cells) showed significantly increased in vitro cytotoxicity against CD19+ CLL targets caused by increased frequencies of CD8+ CART cells...Duv-CART cells significantly enhanced survival of CLL-bearing mice compared with conventionally manufactured CART cells. In summary, exposure of CART to a PI3Kδ/γ inhibitor during manufacturing enriched the CART product for CD8+ CART cells with stem-like qualities and enhanced efficacy in eliminating CLL in vivo.

In summary, we for the first time observed increased TOX expression concurrent with PD-1, Tim-3, and CD244 on T cells, which may contribute to T cell exhaustion and impair their function in MM. Thus, TOX may be considered a potential target for reversing T cell exhaustion and improving T cell function in MM.

Biliary tract cancer cells differentially express galectin-9 and its receptor, TIM-3, in vitro . Higher plasma levels of soluble galectin-9 are associated with worse overall survival, suggesting galectin-9 expression may be related to a more aggressive disease state. Additional work is needed to better inform the mechanistic role of the galectin-9/TIM-3 axis on disease progression and how best to leverage this pathway as a therapeutic target in the management of biliary tract cancers.

Increases in CTLA-4 and TIM-3 expression in CD4+ T cells (not CD8+), as well as an increase in Th17 cells, may reflect asthma-related inflammation activity. Immune-related adverse events during immune checkpoint inhibitor administration may be predictive markers of antitumor efficacy.

IHC protein staining, in vitro and in vivo experiments verified the results of bioinformatics analysis. In gliomas, 1p/19q codeletion can promote the antitumor immune response by downregulating the expression levels of the immune checkpoint TIM-3 and its ligand Galectin-9.

Immunofluorescence revealed a higher density of PD-1 /CD8 cells in the tumor center in this group. Our findings identify a subset of MSS CRC that exhibits evidence of higher prior immune activation (MSS-ImmEx ) in which therapies targeting Tim-3 in conjunction with anti-PD-1 or other immunotherapies may provide clinical benefit.

Although observing its antiproliferative effects, these negative effects may be related to the cells being resistant to the drug or the remaining cells having a more aggressive phenotype. Therefore, we think that caution should be exercised in the use of this drug for CCA treatment.

Of importance, silencing of TIM-3 shuttled by MV3 cells-derived exosomes improved CD4 T cell immune function and inhibited macrophage M2 polarization to attenuate the growth and metastasis of melanoma cells. Collectively, MV3 cells-derived exosomes-loaded TIM-3 suppressed CD4 T cell immune function and induced macrophage M2 polarization to improve occurrence and development of melanoma, therefore providing us with a potential therapeutic target for effectively combating melanoma.

 Early apheresis, after first line of chemotherapy, shows abundance of T lymphocytes, mainly CD8+ cells, with an improved quality of the starting material, represented by a higher percentage of naïve, less exhausted and senescent cells. Furthermore, early apheresis shows a higher T cell proliferation potential. These improved parameters in the initial collected product may have an influence on the manufacturing process and eventually on the efficacy of the infused CAR T cells.

 Taken together, the data show that the addition of aSF7-mAb to shield SLAMF7 on T cells substantially facilitates the manufacturing of SLAMF7 CAR T cells for adoptive therapy of multiple myeloma. The prevention (or rather: the steering of controlled fratricide) leads to increased yield, augmented phenotype and anti-myeloma function in pre-clinical models. These data suggest that SLAMF7 CAR T cells produced with this improved protocol will also confer superior anti-myeloma efficacy in a clinical setting. The aSF7-mAb is available in pharmaceutical grade and be seamlessly incorporated into cGMP manufacturing processes for the next generation of trials under the CARAMBA IND.

HIV-1 and HHV-8 viral loads were measured in plasma by quantitative PCR.BAL T cells showed reduced inflammatory capacities and significantly diminished polyfunctionality compared to blood T cells from patients with pKS. This was not accompanied by increased expression of exhaustion markers, such as TIM-3 and PD-1.More importantly, we found a negative correlation between the production of MIP1-β and TNF-α in T cells in BAL and blood, indicating compartmentalised immune responses to pKS and accentuated chronic HIV-1/HHV-8 pathogenesis via T cells in the lungs of people with pKS.

Approximately 30% of late-stage tumors exhibited highly infiltrated cytotoxic T cells with high PD-1 and FOXP3 expression, which implied that cytotoxic T cells were inhibited in the advanced UC microenvironment. Collectively, our findings provide a better prognosis prediction by combined immune checkpoint biomarkers and a basis for early-stage UC standard treatment to convert cold tumors into hot tumors, followed by immune checkpoint therapy.

The mir-30d/TIMP3 signaling pathway plays an important regulatory role in pituitary adenomas. These new discoveries may reveal more functions of miR-30d and lay the foundation for future clinical development of new drug targets.

The results showed higher sTIM-3 and SCCAg levels in the OSCC patients and better diagnostic potential for a combination of these markers than for their individual assessments, as well as positive correlation of sTIM-3 levels with clinicopathological factors. sTIM-3 is a potential novel and readily accessible OSCC biomarker, which in combination with SCCAg expression level might better diagnose OSCC patients.

We validated this finding in an independent cohort of metastatic melanoma patients treated with intralesional or systemic IL-2. Our study suggests that intact tumor cell antigen presentation is required for melanoma response to IL-2 and describes a multi-dimensional and spatial approach to develop immuno-oncology biomarker hypotheses using routinely collected clinical biospecimens.

Kaplan-Meier survival analysis showed that Tim3 expression in colorectal cancer and in TILs was significantly associated with patient overall survival (OS) rate (P=0.039, and 0.001). Tim3 may be a potential prognostic marker and a therapy target for colorectal cancer.

We find that Vγ2Vδ2 T cells express PD-1, CTLA-4, LAG-3, and TIM-3 inhibitory receptors during the 14-day ex vivo expansion period, and PD-1, LAG-3, and TIM-3 upon subsequent stimulation by pamidronate-treated tumor cells...Importantly, anti-PD-1 mAb treatment enhanced Vγ2Vδ2 T cell immunity to PC-3 tumors in immunodeficient NSG mice, reducing tumor volume nearly to zero after 5 weeks. These results demonstrate that PD-1 checkpoint blockade can enhance the effectiveness of adoptive immunotherapy with human γδ T cells in treating prostate tumors in a preclinical model.

Importantly, PD-1 blocked with anti-PD-1 antibody effectively improved the effector function of NKT-like cells from HCC patients or healthy donors. Our findings unveil the functional characterization of NKT-like cells in HCC patients and provide the potential targets to improve their function, which might benefit the optimization of HCC immunotherapy.

Our findings suggest that LAG-3 may become a biomarker in highly malignant breast cancers such as TNBC and HER2BC that can predict the therapeutic efficacy of NAC.

Taken together, our data suggest that HNSCC might down-regulate Bat3 expression to augment Tim-3 signaling and ultimately suppress the tumoricidal activity of NK cells. This study unveils a novel mechanism by which HNSCC evades NK cell killing, and sheds light on designing novel anti-HNSCC immunotherapy targeting Bat3 and Tim-3 signaling.

Low-risk patients had a higher PD-1, CTLA-4, and HAVCR2 expression and had a better efficacy of immune checkpoint inhibitors, including PD-1/CTLA-4 inhibitor. A reliable signature on the basis of ARlncRNAs was constructed to explore the TIME and prognosis of patients with LUAD, which could provide valuable information for individualized LUAD treatment.

Modulation of the TIM-3/Gal-9 checkpoint is a promising approach for the treatment of cancers and the role of lactose in this context is discussed. The review highlights the immuno-regulatory functions of lactose, and the benefit of the molecule well beyond its use as a pharmaceutical excipient.

The results of our study suggest that exosome-related risk model was related to the prognosis and ratio of immune cell infiltration in patients with TNBC. This discovery may make contributions to improve immunotherapy for TNBC.

The obtained results indicated that miR-155 upregulation in M during HCV infection enhances the activation of TNF-α and JNK pathways, promotes the expression of transcription factor T-bet, and triggers pro- and anti-inflammatory mediators. Together, these data reveal new information regarding the mechanisms of chronic HCV infection.

Increased TOX concurrent with PD-1, Tim-3, and CD244 in T cells may contribute to T cell exhaustion and impair their function in AML. Such exhausted T cells may be partially revised when AML patients achieve CR after chemotherapy. TOX may be considered a potential target for reversing T cell exhaustion and improving T cell function in AML.

CHI3L1 contributes to tumor progression by stimulating the PD-1/PD-L1 axis and other checkpoint molecules. The simultaneous targeting of CHI3L1 and the PD-1/PD-L1 axis with individual and, more powerfully, with bispecific antibodies represents a promising therapy for pulmonary metastasis and progression.

To our knowledge, this is the first study which demonstrates hepatic CD169 macrophages as a key factor responsible for RFA-induced abscopal effect. Our data suggest RFA with transfer of CD169 macrophages as a promising combination therapy to lessen metastasis or recurrence of liver cancer in patients.

While clinical trials of anti-PD-1 therapy have not shown promise in uLMS, the significant co-expression of Gal-9 in PD-L1-positive cases indicates that the TIM-3/Gal-9 axis may be involved in immune evasion in these tumors. Thus, it may be worth investigating the action of anti-TIM-3 agents in uLMS. The loss of MHC expression was identified in a majority of cases, indicating that this may be a pathway of immune escape in uLMS.

Our research demonstrates that HAVCR2/TIM3 was closely related to CD8+TILs both in protein and gene level, and exhibited an inferior OS in AITL. The function of HAVCR2/TIM3 could be regulated by some transcriptional genes, and the synergistic action of HAVCR2/TIM3 and other inhibitory receptors might lead to CD8+TILs exhaustion in AITL and result in poor prognosis, which indicate HAVCR2/TIM3 could be a novel target in AITL therapy and deserve further research.

Pancreatic ductal adenocarcinoma (PDAC), one of the most deadly digestive cancers, has a poor 5-year survival rate and is resistant to chemotherapeutic agents, such as gemcitabine...We also found a positive correlation between Notch3 mRNA expression and TIMP3 expression in patients with PDAC. We concluded that blocking Notch3/TIMP3 pathway could considered a potentially new therapeutic strategy for treating PDAC.

Through the correlation between risk score and immune checkpoint expression, T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) was predicted as a potential therapeutic target for the high-risk group. The 13-gene signature was associated with OS, immune cells, tumor purity, and immune checkpoints in CC patients, and it could provide the basis for immunotherapy and predicting prognosis and help clinicians make decisions for individualized treatment.

Our results revealed that BM-resident γδ T cells in AML and MM express TIGIT, PD-1, TIM-3 and CD39. As effector population for autologous and allogeneic strategies, inhibition of co-inhibitory receptors on especially Vδ1 γδ T cells may lead to re-invigoration that could further increase their cytotoxic potential.

In sequential samples (before and after nivolumab therapy) an increase in PD-1 (p = 0.011) and LAG-3 (p = 0.0045) and a depletion of CD68 (p = 0.057) and CD163 (p = 0.0049)-positive cells were observed. The study expands understanding of the cHL microenvironment structure and dynamics during nivolumab therapy in patients with r/r cHL.

T cells were negatively selected using MACS beads and transduced with CD19 CAR lentivirus (encoding CD28 or 41BB co-stimulatory domains) and stimulated with anti-CD3/CD28 beads in media containing 30 U/mL interleukin-2 with or without the PI3Kδ/γ inhibitor duvelisib (Duv) for 15 days... Inhibition of PI3Kd/g during CART cell culture decreased the expression of immune checkpoint molecules and enhanced in vivo expansion leading to greater efficacy in eliminating CLL.

The infiltration of cytotoxic T cells into tumours is a critical factor in immunotherapy efficacy. Here we clearly demonstrate the feasibility of mIHC to describe the spatial context of the iTME and we plan to implement it for predictive value in future studies of immunotherapies in patients with MM. Figure 1 : Bone marrow FFPE trephine section stained with mIHC using the Opal TM workflow demonstrating plasma cells (CD138, green), T cells (CD3, yellow; CD8, pink) and checkpoint receptors (PD-1, orange; Lag-3, magenta; Tim3, light blue) with colocalisation of some signals.

In vivo studies confirmed that depletion of CD4 T cells completely abrogated the inhibition of tumor growth and metastasis, as well as the functional improvement of CD8 T and NK, mediated by Tim-3 blockade, which was further validated in peripheral lymphocytes from patients with hepatocellular carcinoma. In conclusion, our findings unravel the importance of CD4 T cells in Tim-3/Tim-3L mediated immunosuppression and provide new thoughts for Tim-3 targeted cancer immunotherapy.

Our study inspires new ideas for the role of TIMPs in GBM and provides new directions for multiple treatment modalities, including immunotherapy, in GBM.

In stage 2 (SL-701 + bevacizumab + poly-ICLC) the overall survival at 12 months was 50%. By week 24, SL-701-induced target-specific CD8+ T cells expressing IFNg were detected in 8 of 27 patients (30%) who had sufficient samples, with co-expression of PD-1, TIM3, and LAG3 detected in 4 patients. To further understand the T-cell response to SL-701, deep sequencing of target-specific CD8+ T cells using whole transcriptome-based molecular cytometry and high parameter (25+ color) flow cytometry is currently underway and updated data will be reported.

This study indicates that TILs with high expression of TIM3 may contribute to immunosuppression in the tumor microenvironment of fibroblastic tumors. Patients with fibroblastic tumors with high expression of PD1/PDL1 and TIM3 may therefore benefit from combination therapy with PD1/PDL1 and TIM3 inhibitors.

In addition, the noteworthy expansion of TIM3+ memory CD8 cells in FL. Targeting these most highly expressed checkpoints in FL alone or in combination may provide an avenue for rational trial design.

Our findings suggest that the proven clinical effect of monoclonal antibodies against TIGIT and TIM-3 in cancer may be due in part to their action on macrophages and depend on macrophage polarization. Our study identifies TIGIT + M2 LAMs co-expressing TIM-3 and LAG-3 as a promising effector population in AML. Further experiments should be conducted to investigate macrophage-mediated cytotoxicity in AML.

One patient was analysed at diagnosis and then again after achieving MMR following dasatinib treatment for 11 months...Similarly, another patient was analysed whilst in MMR and then again following haematologic relapse, one week after regaining CHR with ponatinib... Samples from 22 patients were analysed, including samples from two different time points in 4 patients. This included patients at diagnosis (n=8), those with refractory disease defined as <CCyR (n=3) and those with a response of MMR (n=6) and MR4 or greater (n=9). Patients with a response of MMR or greater were considered to have low disease burden.

In vitro, AML cell lines with Tim-3 p.Y82C overexpression revealed lower Tim-3 expression and apoptotic rate as well as lower sensitivity to cytarabine. The bioinformatic analysis also indicated Tim-3 low expression was associated with lower survival in AML patients (P=0.0009). Our findings provide new viewpoint that Tim-3 mutation results in Tim-3 lower expression and is a poor prognostic factor in AML.

In summary, our findings identify that changes to CD19 glycosylation, either enhanced or decreased, impair the ability of CARs to bind and initiate T cell effector function against malignant B cells. Further, these data identify post-translational protein modification as a novel mechanism of antigen escape from CAR-based T cell immunotherapy.

Additionally, T-cell function was assessed after stimulation with 1) CD3/CD28 beads; 2) AMG 330, a CD33/CD3 specific BiTE ® construct, after incubation with OCI-AML3 target cells; or 3) AMG 330 in an autologous ex vivo long-term culture system after incubation with primary AML cells (pAML)...These observations may highlight the significant role of the AML target cells in shaping a T-cell response. To this end, we will further analyze the longitudinal communication between T cells and their corresponding AML blasts.

Methods We analyzed the effects of anti-TIM3 (sabatolimab, MBG453) in combination with decitabine in 11 refractory/relapsed AML patients and 1 MDS patient recruited in a phase Ib trial (NCT03066648), with 5/12 responders (3 CR, 2 CRi). In responding patients, NFκB pathway was activated in T/NK cells following anti-TIM3 and HMA treatment concomitant with a decrease in inhibitory interactions. Our results pinpoint the differential effects of TIM3-blockade on immune cells and may aid in developing predictive biomarkers for treatment outcome.

Thus, modulating the balance among adaptive and innate immune responses was identified as a key process underlying PA-MSHA-mediated treatment efficacy. The results demonstrated mechanisms underlying intravesical PA-MSHA therapy, pointing at its potential as an alternative effective treatment for NMIBC.

We developed and validated a machine learning-based predictor for OS and PFS that outperforms standard Cox predictors in HPV-negative HNSCC. This study provides a rationale to use the predictor as a stratifier in a prospective clinical trial of surgery, radiotherapy, and PD1 blockade in patients with microscopic ENE and intermediate-risk disease.

Funding Czech Science Foundation (grant No. 19-04099S); Ministry of Health, Czech Republic (project for conceptual development of the research organization No 00023736).

Legal entity responsible for the study Egor Batorov. Funding Russian Science Foundation (grant nr: 20-75-10132).

We developed and validated a machine learning-based predictor for OS and PFS that outperforms standard Cox predictors in HPV-negative HNSCC. This study provides a rationale to use the predictor as a stratifier in a prospective clinical trial of surgery, radiotherapy, and PD1 blockade in patients with microscopic ENE and intermediate-risk disease.

The optimal concentration ratio for producing TGF-β1-loaded chitosan NPs was 2:1, with less toxicity. The composite NPs suppressed malignant characteristics of CC cells through down-regulation of miR-155 and activation of Tim-3 signal pathway on the surface of macrophages, promoting secretion of macrophage inflammatory factors.

In this review, we summarize the biological functions of TIM-3 and its contribution as it relates to leukemias. We also discuss the effects of TIM-3 blockade in hematological malignancies and clinical trials of TIM-3 for leukemia therapy.

In GC, PD-1, LAG3, and TIM3 expression is positively correlated and associated with better prognosis. Our study provides information for the application of effective immune checkpoint inhibitors against GC.

These results show that Curcumin reinvigorates defective T cells via multiple (PD-1 and TIM-3) and multi-level (IC receptors and its ligands) IC axis suppression, thus providing a rationale to combine Curcumin with conventional targeted therapy or ICB as a multi-faceted approach for treating patients with HNSCC.

These results suggested that LAG3, TIM3 and A2aR are overexpressed in AdCC and MEC, may promote migration of SACC-LM cell and correlated with TGF-β1 and oncogenic signaling pathways.

Our study suggests that although the number of infiltrating T cells is not associated with patient survival, the nature of the infiltrating T cells, resolved in distinct TIL immunotypes, is prognostically relevant in NSCLC and may inform therapeutic approaches to clinical care.

Taken together, our findings identified a new mechanism by which TIM3 induces tumor-promoting M2-like macrophage polarization in TC. Furthermore, TIM3 interference might be a potential tool for treatment of patients with ATC.

Given the heterogeneity of released factors within the TME, it is clear that TGFβ stimulation represents a model to prove TIMP's new properties, but it cannot be envisaged as a soloist NK cell polarizing agent. Therefore, further studies from the scientific community will help defining TIMPs immunomodulatory activities of NK cells in cancer, and their possible future diagnostic-therapeutic roles.

High expression of ICs was associated with poor OS of patients with ESCC. PD-L1/TIM3 and PD-L1/TIGIT were the optimal combinations for predicting OS, which might be potential targets for future ICBs therapy of ESCC.

Patients with high prognostic risk had higher resistance to some chemotherapy and targeted drugs, such as methotrexate, vinblastine and erlotinib, than those with low prognostic risk (P < 0.05). In addition, knockdown of SMG5 and MRPL9 was determined to significantly inhibit cell proliferation and migration in HCC. Our study helps to select patients suitable for chemotherapy, targeted drugs and immunotherapy and provide new ideas for developing treatment strategies to improve disease outcomes in HCC patients.

Our results confirmed that lenvatinib is capable of improving patients' immune status, saving the effector cells from exhaustion status and inhibiting the number and function of immunosuppressive cells. The novel index CTL/Treg ratio qualifies as a predictor for the outcome of patients with lenvatinib therapy.

TACE is associated with lower IT density of immune-exhausted effector cytotoxic and T-regs, with significant upregulation of pro-inflammatory pathways. This highlights the pleiotropic effects of TACE in modulating the tumor microenvironment and strengthens the rationale for developing immunotherapy alongside TACE.

Thus, we propose that Tim-3 regulates anti-tumor immunity at least in part through enhancement of Treg function. To our knowledge, this is the first example in which expression of a single co-stimulatory molecule is sufficient to drive differentiation of Treg in this manner.

Enhancement of the activated CD8+ T cell response in mice treated with NKTR-262 in combination with BEMPEG suggests that intratumoral TLR stimulation provides superior antigen presentation and costimulatory activity compared to RT. A clinical trial of BEMPEG/NKTR-262 for patients with metastatic solid tumors is in progress (NCT03435640).

Methods Advanced NSCLC pts with available archived tumor tissue at screening visit (VS), treated with standard PD1/L1 ICIs (nivolumab, pembrolizumab or atezolizumab), alone (2nd line or more) or combined with chemotherapy (1st line), were re-biopsied at 6 weeks (V2) of treatment. Additional tests performed on the PIONeeR cohort to explore other aspects of the immune response to cancer should complete these results. Trial Registration NCT03493581

Neuroendocrine tumors were the least immunogenic, with frequent high expression in only 4/36 genes, including ADORA2A (42%) and MAGEA1 (37%). Conclusions CUP tumors diversely express both standard marker and novel immunotherapeutic targets based on histology and may benefit from selective access to clinical trials for these therapies.

Conclusions Our data uncovered TIM-3 as a potential target for the treatment of DIPG tumors. Inhibition of this molecule led to a potent antitumor effect mediated by a profound tumor microenvironment remodelling.

Conclusions Overall, our data suggest that CD39 expression on CD8+PD-1hi EC-resident T cells defines a tumor-reactive population that plays an important role in protecting patients from recurrence after surgery. However, PD-1 expression but not CD39 on CD4+ TILs, better guides the identification of lymphocyte subsets with enriched tumor-recognition potential that contribute to improved clinical benefit in EC.

Although the exhausted PD-1 expressing T cells were detected in 28.3% of T cells, the double positive of PD-1 and TIM-3 T cells were rarely detected. In summary, the TIM-3 levels on AML blasts and NK cells are potentially the prognostic biomarkers in AML.

Furthermore, we demonstrated that lenalidomide, nivolumab and atezolizumab improved ex vivo response to BsAb by potentiating T cell effector functions. In summary, our ex vivo study identifies a distinct regulatory T cell phenotype as potential contributor to treatment failure of BsAb, and suggests drug combinations of high clinical relevance that could improve the efficacy of BsAb.

Moreover, a high risk score correlated with the infiltration immune cells (dendritic cells, macrophages, CD4+ T cells, and B cells) and expression of immune checkpoint (PD1, PDL1, TIM3, and CD48). Our prognostic model was based on iron metabolism-related genes in LGG, can potentially aid in LGG prognosis, and provides potential targets against gliomas.

Mechanistically, 4.1R regulated CAR T cell function via activating ERK signaling pathway. Therefore, the study provides a new idea to enhance the anti-tumor efficiency of CAR T therapy.

In summary, our results identify impaired SARS-CoV-2 T cell immunity as a determinant for poor outcome of COVID-19 in cancer patients, particularly in HM. These findings guide the development of therapeutic measures and vaccines for this vulnerable patient population.

No abstract available

Notably, the surface of Tfr cells of TNBC patients had higher levels of TIM-3 expression than those of healthy control patients (3.93±0.92 vs. 2.65±0.15, respectively; t=-3.02; P<0.05), which the mass spectrometry showed were positively correlated with the intracellular Foxp3 expression of Tfr cells (r=0.82; P=0.036). Our results suggest that circulating Tfr cells and the expression of TIM-3 were significantly increased in BC patients, which were related to stage and histological type, and may be involved in the pathogenesis of BC.

CD39+CD8+ circulating T cells have preserved effector function, contributing to an improved prognosis and a reduced risk of metastasis among NPC patients. These cells may thus be a useful predictive marker for a better prognosis in patients with NPC.

In this cohort study, we treated 60 patients with axicabtagene ciloleucel or tisagenlecleucel. Furthermore, higher CMR/PMR rates were observed in patients with a higher maximal in vivo expansion of CAR T-cells (p = 0.05) and lower expression of the LAG3 and Tim3 markers of exhaustion phenotype (p = 0.01 and p = 0.04). Thus, we find that aaIPI at the time of infusion, phenotype of the CAR T product, in vivo CAR T-cell expansion, and low levels of LAG3/Tim3 are associated with the efficacy of CAR T-cell therapy in DLBCL patients.

Therefore, Tim-3 is being regarded as a high-potential target for improving breast cancer therapy. In this review, we summarize the role of Tim-3 in breast cancer and the regulation mechanisms of Tim-3 to furnish evidences for future research and therapy.

We highlighted the clinical and transcriptomic significance of T in patients with HNSCC. Further characterization of T could lead to the development of novel biomarkers, especially for immune checkpoint therapies.

hILC1s are increased in higher stage tumors among patients with muscle-invasive bladder cancer. These intratumoral hILC1s exhibit an exhausted phenotype and Th17-like differentiation, identifying them as potential targets for immunotherapy.

Précis. Homeostatic proliferation plays apparently a key role in the upregulation of PD-1 and TIM-3 on functional T cells after AHSCT and appears to be a normal physiological process, contrary to relapse-associated increase in PD-1 and TIM-3 T cells.

Pre-treatment with TACE is associated by lower intra-tumoral density of immuneexhausted effector and regulatory T-cells, with significant up-regulation of pro-inflammatory pathways. This highlights the pleiotropic effects of TACE in modulating the tumour microenvironment and strengthens the rationale for developing immunotherapy alongside TACE to improve outcomes of HCC patients.

Multiplex IHC is a novel technique to assess the iTME. While there is no discernible quantitative difference in cytotoxic T-cells or checkpoint receptor expression, we demonstrate increased proximity of cytotoxic T- cells to plasma cells in newly diagnosed patients suggestive of a more robust immune system compared to multiply treated patients.

Spartalizumab demonstrated a safety profile consistent with other anti-PD-1 antibodies. The primary endpoint of median PFS was not met, however , median OS and median DOR were longer with spartalizumab compared with chemotherapy.

High risk scores correlated significantly negatively with high CTLA-4 and HAVCR2 expression and higher median inhibitory concentration of common anti-tumor chemotherapeutics (e.g., cisplatin, paclitaxel, gemcitabine) and targeted therapy (e.g., erlotinib and gefitinib). We identified a reliable immune-related lncRNA lung adenocarcinoma prognosis model, and the immune-related lncRNA signature showed promising clinical prediction value.

The seven m6A-related lncRNAs prognostic risk signature showed reliable prognostic predictive power for ccRCC and was associated with the expression of immune checkpoints and immune cell infiltration. This seven m6A-related lncRNAs signature will be helpful in managing ccRCC and guiding individualized immunotherapy.

Our study showed that PAX5 haploinsufficiency induced CD8+ T cells dysfunction or exhaustion by high expression of TIM3, NR4A1 and BATF in the CD8+ T cells of TME.

Further, concurrent high frequencies of T + NK-TIM-3 and CD34CD38TIM-3 cells at diagnosis were significantly associated with a high 2-year CIR (p < 0.0001) and this together with c-KIT D816 mutation were the independent adverse prognostic factors for relapse (hazard ratio (HR)=2.5, &lsqb;95% confidence interval (CI), 1.1-6.0], p = 0.04; HR = 46.5, &lsqb;95% CI, 2.7-811.5], p = 0.009). In conclusion, the expression pattern of TIM-3 on both T and NK cells and LSCs at diagnosis had prognostic significance in t (8;21) AML.

Our results indicate that expression of TIM-3 and CEACAM1 may represent a highly dysfunctional population of T cells. Our current findings suggest both of them were valuable predicting markers that might provide help for clinicians to design effective immunotherapeutic regimen against head and neck carcinoma.

TIGITTIM-3NK cells showed exhausted phenotypic characteristics and displayed dysfunction manifested as weakened killing function, reduced cytokine production, and proliferation function. TIGITTIM-3NK cells participate in NK cells function exhaustion and are closely related to the disease progression of patients with HBV-HCC, suggesting a new target for future immunotherapy.

have shown that nivolumab is effective and safe in HNSCC patients ≥65 years old...Transcriptional and immunologic signatures identified senescence rather than terminal exhaustion as the crucial dysfunctional state and TIM-3 as the major checkpoint receptor elevated in the aging HNSCC population. These data suggest that older HNSCC patients may benefit from PD-1 + TIM-3 combination ICBs and from emerging therapies targeting the reversal of T cell senescence

We confirmed that high Tim-3 protein expression can be used as an indicator of earlier IVR and shorter OS in patients with UTUC, while high expression of PD-1 is only related to earlier IVR. We showed that Tim-3 plays a more important role in tumour recurrence and progression than PD-1. Collectively, our findings support the use of Tim-3 and PD-1 as clinical prognostic factors indicating poor patient survival. Tim-3, alone or in combination with PD-1, could become a target for future UTUC therapies, but further prospective studies are needed.

By the negative regulation of CD4 T cells, activated Galectin-9/Tim-3 suppresses Th1 effector function and also promotes Treg to be involved in immune escape of CLL. This pathway might become the potential target of immunotherapy in CLL patients.

In conclusion, our data provide evidence for the superior potential of the SCLC cells with stem-like and mesenchymal properties to gain immune regulatory capacities and cope with cytotoxic T cell responses. With their high metastatic and immune-modulatory assets, the CSC subpopulation in SCLC may serve as a preferential target for checkpoint blockade immunotherapy .

The current study provided evidence that blood gene expression of ICs was up-regulated in CRC patients and associated with cancer stage and patients' survival, which highlights the diagnostic and prognostic values of ICs expression in CRC. Further investigations and validations in larger cohorts are required.

A subset of localized PCa is immunogenic, manifested by PD-L1 expression and CD8 T cell content comparable to RCC. The CD8 T cells include effector cells and exhausted progenitor cells, which may be expanded by ICIs. Genomic losses of RB1, BRCA2, and CHD1 may be drivers of this phenotype. These findings indicate that immunotherapies may be effective in biomarker-selected subpopulations of localized PCa patients.

The proposed immune relevant model is a promising biomarker for predicting overall survival in stage I-III LUSC. Thus, it may shed light on identifying patient subset at high risk of adverse prognosis from an immunological perspective.

Further analysis found that IL-10 upregulated TIGIT expression on NK cells. Thus, TIGIT blockade alone or in combination with other therapy might be potential strategy to treat AML.

We describe positive exposure-PFS and exposure-OS relationships for pembrolizumab in metastatic melanoma. TIM-3, alongside co-expression of CXCR6 and TIM-3 on circulating CD4 T cells are potential bio markers of treatment failure.

In the LYSA trial GATA (NCT03276468), 58 DLBCL and 58 FL R/R patients were treated by obinutuzumab (OBI) combined with BCL-2 inhibitor venetoclax (VEN) and anti-PDL1 atezolizumab (ATE) in order to test the synergy of chemo-free tumor-targeted therapies. We show herein that TME composition and ICP expression are distinct between R/R FL and R/R DLBCL and remain mostly unchanged after R-chemotherapy compared to initial biopsies, except for higher TIM3 and TIGIT expression levels. This preliminary study indicates that high expression of TIGIT in R/R DLBCL and TIM3 in R/R FL patients are correlated with responsiveness following OBI-VEN-ATE therapy. Thus, TIGIT and TIM3 expression could predict the efficacy of PD1/PD-L1 blockade in these settings.

P2, N=65, Active, not recruiting, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano | Recruiting --> Active, not recruiting | Trial completion date: May 2021 --> May 2022 | Trial primary completion date: May 2021 --> May 2022

TIMP1 and TIMP2 could be used as diagnostic biomarkers in GC. TIMP2 and TIMP3 could be used as potential biomarkers for GC's prognosis.

Tumor-bearing animals were treated with human-equivalent dosages of doxorubicin, paclitaxel, paclitaxel and carboplatin combination, and placebo. Our findings hypothesize that NAC with doxorubicin may potentiate antitumor immunity not merely by recruitment of TILs, but via down-regulation of PD-1 and TIM-3 checkpoints. Carboplatin-containing NAC may suppress PD-1 as well.

In addition, γδ T cells from CHB patients expressed increased levels of CD69, another important regulator of immune responses. Together, these results suggest that CHB patients with clinical sign of liver disease have T γδ T cells with a potentially exhausted phenotype that may in turn impair their immunoregulatory role and facilitate pathogenesis of CHB disease.

The new generation ICRs, TIM-3, LAG-3, and TIGIT are highly expressed in LABC following NAC in patients with poor prognostic factors. Therefore, new evolving therapies using inhibitory mAbs directed to TIM-3, LAG-3, and TIGIT could be also be considered in locally advanced breast cancers expressing these ICRs.

These findings were not more pronounced in patients with an alkaline phosphatase response during therapy. Immune cell subsets in patients with mCRPC changed during radium-223 therapy, which warrants further research into the possible immunological consequences of these changes.

Multivariate analyses performed after adjusting for clinical variables showed that patients with the CA+AA genotypes of rs10053538 exhibited a significantly shorter disease-free survival (DFS) and overall survival (OS) time compared with those carrying the CC genotype (HR = 1.91, 95% CI = 1.04-3.51; HR = 2.61, 95% CI = 1.35-5.03). In addition, the expression of TIM-3 mRNA was significantly increased in the CRC tissues of patients carrying the rs10053538 CA+AA genotypes compared with patients carrying the CC genotype (P = .019). The rs10053538 may serve as an independent molecular marker for predicting the clinical outcome of CRC patients in the study population.

In conclusion, the addition of durvalumab to daratumumab following development of daratumumab-resistance was associated with an acceptable toxicity profile, but was not effective. This indicates that inhibition of the PD-1/PD-L1 signaling pathway at the time of daratumumab-resistance is insufficient to reverse daratumumab-resistance.

Although IDO generally inhibits T-cell proliferation, a high expression of IDO was associated with improved survival. We expect immune checkpoint inhibitors against VISTA, LAG3, and TIM3 to be inefficient in a clinical application.

In line with this, stimulated PD1+TIM3+ TILs from DLBCL patients exhibited reduced proliferation and impaired secretion of interferon-γ, but these functions were restored by the blockade of PD1 or TIM3. In summary, the PD1+TIM3+ TIL population is expanded and exhausted in DLBCL but can be reinvigorated with appropriate therapies.

Finally, CMs from PCa circulating NKs recruit THP-1 and peripheral blood CD14+ monocyte and polarize THP-1 and peripheral blood CD14+ monocyte-derived macrophage towards M2-like/TAM macrophages. Conclusion Our data indicate that circulating NK cells from PCa patients can contribute to PCa progression by supporting angiogenesis and macrophage M2-like polarization.

Finally, CMs from PCa circulating NKs recruit THP-1 and peripheral blood CD14+ monocyte and polarize THP-1 and peripheral blood CD14+ monocyte-derived macrophage towards M2-like/TAM macrophages. Conclusion Our data indicate that circulating NK cells from PCa patients can contribute to PCa progression by supporting angiogenesis and macrophage M2-like polarization.

Finally, CMs from PCa circulating NKs recruit THP-1 and peripheral blood CD14+ monocyte and polarize THP-1 and peripheral blood CD14+ monocyte-derived macrophage towards M2-like/TAM macrophages. Conclusion Our data indicate that circulating NK cells from PCa patients can contribute to PCa progression by supporting angiogenesis and macrophage M2-like polarization.

Finally, CMs from PCa circulating NKs recruit THP-1 and peripheral blood CD14+ monocyte and polarize THP-1 and peripheral blood CD14+ monocyte-derived macrophage towards M2-like/TAM macrophages. Conclusion Our data indicate that circulating NK cells from PCa patients can contribute to PCa progression by supporting angiogenesis and macrophage M2-like polarization.

NACT induces significant IME changes in TNBCs. PD-L1 and TIM-3 expression post-NACT may yield important prognostic information for TNBC patients.

TIGIT+TIM-3+NK cells participate in NK cells function exhaustion and are closely related to the disease progression of patients with HBV-HCC, suggesting a new target for future immunotherapy.

Thus, we propose that Tim-3 regulates anti-tumor immunity at least in part through enhancement of T reg function. To our knowledge, this is the first example in which expression of a single co-stimulatory molecule is sufficient to drive differentiation of T reg and alter immune response in this manner.

Our work revealed NK cells with memory like and stemness features that are helpful in fighting viral infection. We also detected subpopulations in NK memory stem cells and efforts are ongoing to evaluate the role of these NK subpopulations in antiviral immunity.

DLBCL further lack protective stem-like CD8 T-cell subsets which correlate with poor clinical outcome. These results strengthen our understanding of the cellular defects precluding potent anti-tumor T cell functions in DLBCL and FL.

We tested the panAKT inhibitor MK-2206, mTOR (Rapamycin), PKC (Enzastaurin), RAF (Sorafenib) and ERK (PD98,059). Conclusion A promising direction for further research in AML and MDS is not only blockage of TIM3 signaling by monoclonal antibodies, but also elucidation of pathways leading to TIM3 expression on malignant cells. Further research is required to identify the mechanisms of Akt-mediated TIM3 downregulation.

Background Pivotal trials of Axicabtagene-Ciloleucel (Axi-cel) and Tisagenlecleucel (Tisa-cel) for the treatment of relapsed and refractory (r/r) Diffuse Large B-Cell Lymphoma (DLBCL) demonstrated complete responses in 40%>58% of the patients with accompanied grade ≥3 adverse events in approximately 30% of the patients. We observed relationships of CAR T-cell kinetics, memory subsets and immune checkpoint expression with efficacy. These findings might bear the potential to monitor treatment responses and prevent disease relapse together with other clinical variables.

These findings demonstrate that CTLA-4, PD-1, PDL-1, and TIM-3 were highly expressed in TNBC. Based on these high expression patterns, further studies directed towards combined therapies are warranted in advanced TNBC in future.

Chemokine expression as well as combinatorial efficacy of TIM-3 blockade and paclitaxel chemotherapy were impaired by deletion of Cgas and Sting...Human peripheral blood cDC1s also took up extracellular DNA upon TIM-3 blockade. Thus, TIM-3 regulates endocytosis of extracellular DNA and activation of the cytoplasmic DNA sensing cGAS-STING pathway in cDC1s, with implications for understanding the mechanisms underlying TIM-3 immunotherapy.

Alike in non-cancer convalescents, reduced T cell diversity associated with a more severe course of COVID-19 in cancer patients. Together, our results identify impaired SARS-CoV-2 T cell immunity as determinant for dismal outcome of COVID-19 in cancer patients in particular in patients suffering from HM, which guides development of therapeutic measures and vaccines for this vulnerable patient population.

In conclusion, we used the MACSima™ Imaging System to decipher relevant phenotypes of CD8+ TILs, such as CD39, in different tumor regions. The further development of enrichment strategies of tumor-reactive T cell subsets will ultimately shed light on the feasibility of this approach for clinical use.

Ex vivo, co-blockade of TIGIT and PD1 can improve functionality of CD8+ TILs from HCC-patients that do not respond to single PD1 blockade. Therefore co-blockade of TIGIT/PD1 could be a promising immune therapeutic strategy for this subset of HCC patients.

Mechanistically, the manifestation of STAT3 decreases the expression of Tim-3 and various cytokines in the purified Treg cells from individual PBMCs and the murine melanoma model, limiting the immunosuppression of Treg cells. Our findings indicate that Tim-3 expression on Treg cells within the TME is STAT3-dependent, providing support to STAT3 as a target and enhancing the immunotherapy for patients suffering from melanoma.

Cox regression analysis revealed that LSC frequency at diagnosis is an independent prognostic factor in AML. Assessment of LSCs (CD34/CD38/TIM3) at diagnosis is recommended for refining of AML risk stratification.

We also studied the correlation between TIM-3 expression on NK cells isolated from glioblastoma patient tumors and whole blood samples. This information is shedding further light on the immunomodulatory roles of TIM-3, and is aiding in leveraging this receptor usage in future NK cell-based immunotherapies.

We could also demonstrate robust and efficient specific cytotoxicity of a CD19 expressing B-cell cell line (JeKo-1), compared to CAR19 T-cells without immune checkpoint silencing. Our data demonstrates efficient creation of next generation anti-CD19 CAR T-cells via novel miCAR gene constructs to achieve simultaneous CAR expression and gene silencing of relevant inhibitory receptors.

Our findings indicate a specific preexisting profile of Tim3+ and G9-expressing tumor cells and demonstrated that Tim3+ cells were mainly found intratumorally within 15µm of a NPC cell . The relevance of Tim3+ and G9+ distances reflect a potential marker of their functional interaction . Our results could have important implications for clinical therapeutic strategies .

The expression levels of CCL18, CXCL13 and CCL7 were significantly higher in GBM tissues with high Tim-3 expression than in GBM tissues with low Tim-3 expression. In addition, exploring the relationship between immune cell infiltration and Tim-3 expression suggested that Tim-3 expression was positively related to significant immune cell infiltration.

The Cu-NOTA-RMT3-23 immunoPET imaging results are further mirrored by the immunofluorescent staining studies. These results demonstrate the feasibility of Cu-NOTA-RMT3-23 immunoPET in tracking TIM-3 and highlight a new opportunity to optimize TIM-3-targeted immunotherapies with this novel imaging strategy.

Following relapse after initial CHOP chemotherapy, the patient was successfully treated with cyclosporine A and has remained in remission since, with prophylactic TMP-SMX and no infections. After a poor response to multiple rounds of chemotherapy, she required autologous bone marrow transplant and has been in remission since, with no infectious complications. These cases illuminate an unusual pathological manifestation for BENTA disease, and further suggest that CARD11 GOF mutations can contribute to the development of cutaneous T cell dyscrasias and/or malignancies involving both CD4+ (Sézary syndrome) and CD8+ (SPTCL) lineages, or both (ALLP).

Further work is needed to determine the significance of this variant and its possible relationship with SPTCL-HLH, as well as reanalysis of his exome to determine if he has an alternative variant which may affect TIM-3 expression or downstream pathways. While the patient has improved on etoposide and dexamethasone, he may require maintenance therapy with an immunomodulator to target this immune checkpoint inhibitor or its effectors.

A total of 48 patients with HGSCs, comprising 24 cases that were sensitive and 24 that were resistant to standard paclitaxel and carboplatin chemotherapy, were selected for our initial analysis. A panel of immunomodulatory proteins including B7-H4, IDO1, Tim3, IL-6, and IL-8 are expressed at high levels in HGSCs. These modulators represent novel targets to enhance immunotherapy in patients with HGSCs.

Expression of TIM-3, an emerging immune checkpoint inhibition target, was significantly higher in mucinous CRC, and expression was predicted by mucinous status independently of MSI. These findings should prompt investigation of immune checkpoint signaling in the mucinous tumor microenvironment to clarify the potential for immune checkpoint inhibition in mucinous CRC.

In conclusion, we have identified that PD-1 and ICs LAG-3 presented a trend towards increased expression after NRT, supporting the ICBs and NRT combination as a potential treatment option for local advanced rectal cancer patients. The radiotherapeutic mode and timing of the treatment might significantly affect the expression of ICBs, which indicated that the sequencing and time window of ICBs immunotherapy utility might deserve a high value.

Among anti-MDA5-positive DM patients, Gal-9 could be a promising biomarker for monitoring disease activity, particularly for RP-ILD severity. Aberrant expression of the Gal-9/Tim-3 axis may be involved in the immunopathogenesis of DM-ILD.

It is concluded that TIMP1 (rs4898) and TIMP3 (rs9619311) polymorphisms are not significantly related to breast cancer. Moreover, CC and TT genotypes are correlated with increased serum TIMP1 and TIMP3 levels in breast cancer patients, respectively. It is also suggested that serum concentration of TIMP1 and TIMP3 is related to the physiopathology of breast cancer.

In summary, the immune microenvironments of the immunity-high and immunity-low groups of patients with MIBC are heterogeneous. Specifically, immune suppression was observed in the immune microenvironment of the patients in the immunity-low group.

Our results suggest that TIMP3 is an oncosuppressor in human OS cells. Reactivation of TIMP3 function may be considered as a potential therapy for the treatment of this bone cancer.

Moreover, the CD8+CD39+ T cells showed a stronger tumor-killing effect and produced a higher level of IFN-γ than other T cell populations. CD39 may be a potential prognostic marker in BLCA, and CD8+CD39+ T cells may be selected as tumor-reactive and killing T cells for TILs therapy.

Ex vivo, co-blockade of TIGIT/PD1 improves functionality of CD8 TILs that do not respond to single PD1 blockade. Therefore co-blockade of TIGIT/PD1 could be a promising immune therapeutic strategy for HCC patients.

These results suggest that dual therapy with anti-CTLA-4 and anti-PD-1 antibodies significantly inhibits growth of microsatellite stable CRC by suppressing immunosuppressive checkpoints. Upregulation of TIM3 represents a potential escape mechanism and a target for future combination immunotherapies in CRC.

Upregulation of ICs on OAC cells following chemotherapy may represent potential mechanisms of chemo-immune resistance. Combination ICIs may be required to enhance the efficacy of chemotherapy and immunotherapy in OAC patients.

Here, we show that hepatitis A virus cellular receptor 2 (HAVCR2, best known as TIM-3) is highly expressed by NK cells from AML patients, correlating with improved functional licensing and superior effector functions. Altogether, our data indicate that NK cell frequency as well as TIM-3 expression levels constitute prognostically relevant biomarkers of active immunity against AML.

This triple therapy improves the specific cytotoxic activity and decreased the apoptosis of CD8 TILs. These findings indicated that this triple therapy could induce a more robust anti-tumor immune response.

Therefore, rationality implies that designing novel monoclonal antibodies reactive with Tim-3 alone or in combination with other checkpoint inhibitors may indicate a favorable response in bladder cancer. Here, we aimed to investigate the possibility of targeting Tim-3 as a novel anti-cancer treatment for bladder cancer.

For rs10515746C > A and rs1036199A > C polymorphisms, there were no statistical correlation with the progression of ESCC. These data demonstrate that rs10053538C > A polymorphisms may be associated with the susceptibility and prognosis of ESCC patients through regulating expression of TIM-3.

No abstract available

Three-month Se supplementation did not prevent relapse in Se+ group. Taken together, Se supplementation alone did not affect the frequency of CD4CD25FOXP3 Tregs, expression of checkpoint receptors, and prevention of relapse in DLBCL patients at stable remission phase but might influence the functional properties of other Treg subsets like CD4CD25FOXP3 Tregs.

We describe a positive exposure PFS and exposure OS relationship for pembrolizumab in metastatic melanoma. The data indicate the co-expression of CXCR6 and T-cell exhaustion markers on circulating CD4+ and CD8+ T cells are potential biomarkers of disease progression on single-agent pembrolizumab.

Interestingly, Gal-9 was associated with T cell dysfunction and Treg markers, suggesting that in GC Gal-9 could promote T cell dysfunction and Treg expansion. Our results suggest an association between the Gal-9/Tim-3 pathway with a more aggressive and increased immune suppressive microenvironment and GC.

High TIM-3 expression was significantly associated with lower overall survival rates during the 1-year follow-up (P=0.001). Taken together, the results of the present study suggest that TIM-3 may act as a biomarker of a poor prognosis in patients with AML, and be used as a therapeutic target.

Meanwhile, TIM-3 played a crucial role in tumor immune responses. This supports TIM-3 as a promising target for cancer immunotherapy.

Moreover, myeloid cells from obese mouse tumors had higher expression of PDL1, CD206, and CD38 markers.Our findings provide evidence that obesity impairs antitumor immunity by modulating the relative abundance of intratumoral immune cell populations and their phenotypes to promote immunosuppressive microenvironment. These findings will be validated in subsequent studies and examined in human specimens.

Lymphocyte networks decreased in number but were closer to tumors. Using high-dimensional protein expression data to characterize GEMM models following in situ genetic or therapeutic perturbation is a powerful new platform to investigate tumor-immune interactions.

These data suggest that liver mets are less immunogenic, with fewer T cells and greater distances between CD3+ T cells and melanoma cells, and may account for the poor prognosis of melanoma patients with liver metastases and their reduced response rate to immunotherapy compared to other mets. While liver mets have reduced PD-1 expression, higher Tim3 expression in the liver may provide a therapeutic opportunity to improve outcomes for pts with liver mets by using anti-TIM3 immunotherapy. Overall, these data provide novel insights into the site-specific biology of melanoma mets, heterogeneity in the tumor immune microenvironment, and the need for site specific biomarkers to be considered when selecting treatment targets.

ARID1A deficiency defined a group of HBV related liver cancer patients who had worse outcome due to promotion in cell migration. However, the higher TMB, higher mutation rate in DNA damage pathway, higher expression of TIM3 and upregulated immune activity suggested that they might be beneficial target for immunotherapy.

The integrated analysis of TIM-3, CD8, and CD56 TILs as one biomarker is a reliable independent predictor of prognosis. In conclusion, low densities of TIM-3 TILs are associated with poor survival, and integrated immune biomarkers lead to superior predictors of GIST prognosis.

Moreover, the accumulation of TIGITT cells in tumors was associated with advanced disease, predicted early recurrence, and reduced survival rates in colorectal cancer patients. Our results indicate that TIGIT can be a biological marker for the prognosis of colorectal cancer, and TIGIT can be used as a potential target for treatment.

Our findings suggested that the expression of inhibitory ligands for Tim-3 and Lag-3 on GC cells serve as potential biomarkers to predict the response to anti-PD-1 therapy and the combinatorial immunotherapy with ICIs targeting for PD-1, Tim-3, and Lag-3 has a therapeutic potential for GC patients.

Higher expression of TOX concurrent with PD-1, Tim-3, and CD244 in T cells from patients with B-NHL may contribute to T cell exhaustion and impair their special anti-tumor T cell activity. TOX may be considered a potential target for reversing T cell exhaustion and improving T cell function in hematological malignancies.

To identify T cell exhaustion, it is necessary to evaluate T cells co-expressing PD-1, TIM-3 and other inhibitory signal molecules and to study their functional properties. Sustained functionality of PD-1-positive T cells may explain low efficacy and frequent immune-mediated adverse events during anti-PD-1 therapy in MM.

Clinical trials for anti-TIM-3 therapy in various tumors are in progress, while anti-PD-L1 trials in UCS are ongoing. We found that 70% of PD-L1 positive UCS co-express TIM-3 and its ligand Gal-9. Significantly increased odds of the co-expression of Gal-9 and PD-L1 in tumor cells suggest the involvement of both the PD-1/PD-L1 and TIM-3/Gal-9 axes in UCS and potential interaction between them.

For the first time, we demonstrate a significant difference in expression of immune-response genes in RT vs CLL. In particular, we found upregulation in checkpoint pathway genes PD1, LAG3 and TIM-3. Overexpression of LAG3 in large neoplastic B-cells of RT, specifically in cases clonally-related to CLL is a novel finding that may serve as a diagnostic and prognostic marker.

Furthermore, our results suggested that the infiltration of Tregs and naive B cells was strongly correlated with the T stage, radiation therapy, targeted molecular therapy, and the expression levels of TIM-3 and FOXP3 in GC. The expression pattern of tumor-infiltrating immune cells and immune regulatory factors was systematically depicted in the GC tumor microenvironment, indicating that individualized treatment based on the tumor-infiltrating immune cells and immune regulatory factors may be beneficial to GC patients.

Our results show that PCa pTA-NKs acquire properties related to the pro-inflammatory angiogenesis in endothelial cells, recruit monocytes and polarize macrophage to an M2-like type phenotype. Our data provides a rationale for a potential use of pNK profiling in PCa patients.

In conclusion, high levels of Tim-3 and Galectin-9 in HPV positive cervical cancer patients play roles in the progression of disease by promoting Treg cells to inhibit the cytotoxic function of Th1 and CD8+ T cells. Tim-3/Galectin-9 may serve as a new immunotherapy target for patients with HPV positive cervical cancer.

While ICBs may benefit patients of the CMS1 subtype, for the CMS2, CMS3, and CMS4 subtypes in the high SPS group, STING agonists and immunotherapies targeting the Th17 axis may be beneficial. Finally, the SPS-based nomogram could help advance personalized medical decisions for CRC.

The ratios of Th17/Treg, IL-17/IL-10 and Tim-3Th17/Tim-3Treg increase in MM patients, among which Tim-3Th17/Tim-3Treg is correlated with ISS staging, DS staging, chromosomal abnormalities and sFLCR, which suggesting that Tim-3 is involved in the imbalance of Th17/Treg in MM patients.

In our model, PD1 blockade was suboptimally therapeutic alone. The effect of TIM3 and TIGIT was upregulated on T cells in response to PD1 blockade and anti-tumor activity could be enhanced when these inhibitory receptors were also blocked with antibodies in combination with anti-PD1 therapy.

Pembrolizumab administered from 2 to 5 weeks post-infections significantly aggravated EBV systemic spread and, for the M81 model, significantly increased the mortality of mice...We conclude that PD-1 blockade during acute EBV infections driving strong CD8 T cell priming decompensates T cell development towards immunosuppression. Given the variety of preclinical models available, our models conferred a cautionary note indicating that PD-1 blockade aggravated the progression of EBV PTLD.

The present study is the first work to report LAG-3 upregulation after EGFR-TKI failure in advanced NSCLC, which proposed novel insights for rational use of LAG-3 inhibitors in advanced NSCLC patients with EGFR mutation.

Intratumoral PDPN expression had a correlation with MIBC molecular classification and therapy-related signatures. The novel immune checkpoint PDPN should be considered as a possible immunotherapeutic target for MIBC.

Doxorubicin is a common treatment agent in AML, but it may induce inflammation and up-regulate the TIM3/Gal-9 autocrine loop, consequently can enhance the possibility of disease relapse. Meanwhile, oridonin is capable to inhibit the essential signaling pathways in AML cells and reduce the inflammation and expansion of tumor cells and postpone AML recurrence.

The level of TIM-3 expression on T cells, galectin-9 and the IL-10/IL-17 ratio in the CLL patients increased with the advance of Binet stage. Conclusion The TIM-3/galectin-9 signaling pathway is involved in the negative regulation of T cells in patients with CLL.

The frequency of intranodal CD3CD8, CD3CD8PD-1 and CD3CD8PD-1Ki-67 T cells in N nodes was associated with prolonged progression-free (PFS) and overall survival (OS). These data suggest that CD3CD8TIM-3 T cells may suppress tumor spread to regional lymph nodes but once tumor cells metastasize to lymph nodes, CD3/CD8/PD-1/Ki67 T cells localizing to N nodes may prevent further tumor spread, resulting in prolonged survival.

Our results set forth the importance of skin DC in cancer immunotherapy, and demonstrates that restoring DC function is key to enhancing tumor immunogenicity and subsequently responsiveness to checkpoint blockade therapy.

Our hierarchical clustering results based on the 66-gene expression signature were concordant with results from prior studies. Patient subgroups identified by evaluation of angiogenic and T-effector signature scores exhibit significantly different mutations and immune profiles. These findings require prospective validation in future biomarker-selected clinical trials.

Our hierarchical clustering results based on the 66-gene expression signature were concordant with results from prior studies. Patient subgroups identified by evaluation of angiogenic and T-effector signature scores exhibit significantly different mutations and immune profiles. These findings require prospective validation in future biomarker-selected clinical trials.

Immune checkpoint therapy targeting LAG-3, TIM-3, and/or VISTA could be a promising treatment strategy especially in HPV-related OPSCC. Future clinical trials investigating the efficacy of a checkpoint blockade in consideration of LAG-3, TIM-3, and VISTA expression are required.

High baseline peripheral T-cell count and reduced activation of T and NK cell subsets were associated with improved outcomes. Furthermore, increased post-treatment TIGIT and elevated baseline TIM-3 expression suggest that these may limit the efficacy of pembrolizumab, providing a rationale for combination immunotherapy (PD-1 with TIGIT and/or TIM-3 antibodies) to treat extra-pulmonary G3 NENs.

P2, N=28, Ongoing, AZIENDA OSPEDALIERA AO OSPEDALE NIGUARDA CA' GRANDA

In addition, the levels of PD-L1 and HMGB-1 were significantly higher in AML patients than in healthy subjects. In summary, this study provides knowledge on the cytokine expression patterns by PD-1 and/or TIM-3-expressing Vδ2 T cells in AML patients, and indicates that the upregulation of PD-1 alone is insufficient to indicate functional impairment, and Vδ2 T cells may require anti-TIM-3 inhibition for functional revival.

This work revealed that NAC treatment can substantially downregulate CD4+ and upregulate CD8+ T cell ICP expression as well as deplete the amount of TILs and CD8+ T cells found in breast tumor samples. These findings provide a starting point to study the biological significance of these changes in BC patients.

For the first time, we constructed immune gene-related lncRNA risk models. The risk score may be a new biomarker for tumor immune subtypes and provide molecular targets for glioma immunotherapy.

The majority of HGSC developed into a more inflamed phenotype during progression from primary to recurrent disease, including indications of adaptive immune resistance. This suggests that recurrent tumors may be particularly sensitive to inhibition of adaptive immune resistance mechanisms.

Down-regulation of Tim3 expression can inhibit proliferation and induce apoptosis of MM cells, also has an additive inhibitory effect of bortezomib on NF-κB signaling pathway, then inhibit proliferation and induce apoptosis. Therefore, Tim3 may be a potential target for the treatment of MM.

In vitro, PD-1 blockade enhanced CD4 TIL activation, as evidenced by increased CD154 expression and cytokine secretion, leading to improved dendritic cell maturation and consequently to higher tumor-specific CD8 T-cell proliferation. Our data identify CD4 TIL exhaustion as a player of responsiveness to immune checkpoint blockade.

The targeting of TIM-3 is a promising therapeutic approach in cancers, including hematologic cancers such as myeloid malignancies, which have not benefited much from current immunotherapeutic treatment approaches. We anticipate that with further clinical evaluation, TIM-3 blockade will emerge as an important treatment strategy in myeloid malignancies.

CICSS 3 was associated with improved patient survival (HR 0.57 95% CI 0.42-0.78, p = 0.001). The results suggest that individual and combined high expression of TIM-3, LAG-3, and PD-1 on stromal immune cells are associated with better colorectal cancer prognosis, suggesting there is added value to investigating multiple immune checkpoints simultaneously.

High CD3 TIL and T-cell ICOS expression were associated with favourable prognosis, whereas high TIM-3 expression suggested a poor prognosis. Our findings may confer new insights to improve ESCC outcomes beyond the application of PD-1 blockade.

Multivariate analysis showed the prognosis of patients with metastatic RCC of higher WHO/ISUP grade treated by nivolumab to be significantly worse than that of patients with lower grade (P = 0.026). This study showed that tumour grade significantly correlated with dysfunction of both CD4+ and CD8+ TILs and the efficacy of nivolumab treatment.

The expression of costimulatory molecule Tim3 in NK cells and its subsets of patients with acute myeloid leukemia is down-regulated.

While anti-PD-1 pembrolizumab has recently gained FDA approval for use in recurrent or metastatic cervical cancer, other checkpoint molecules, such as TIGIT and Tim-3 have yet to be fully explored in this disease...Our results may show an overview of the immune response towards precancerous lesions and cervical cancer, perhaps giving an early clue as to whom to administer blocking therapies. The increase of multiple checkpoint markers may aid in identifying patients uniquely responsive to combined antibody therapies.

The increased expression of TIM-3 on CD4+ T cells and CD8+ T cells of patients with cervical carcinoma and HSIL suggests the potential role of TIM-3 in the development and progression of cervical carcinoma, which may be a novel therapy target for cervical carcinoma.

This study demonstrates for the first time that LAG-3 and TIM-3 are nearly always expressed in the microenvironment of classical HL. This may constitute the basis for targeting LAG-3 or TIM-3 in combination with anti-PD-1 antibodies in the treatment of relapsed/refractory HL.

P, N=80, Recruiting, University of Catanzaro

TLR stimulation causes APCs in the tumor microenvironment to upregulate PD-L1 in an NF-κB-mediated fashion, thereby contributing to CD8 T cell exhaustion. The effect of PD‑1 blockade after TLR stimulation might be impaired due to upregulation of other checkpoint inhibitors.

TCGA data confirmed lower TIM-3 mRNA expression in IDH-mutant compared to IDH-wildtype astrocytic gliomas (P= 0.013). Our results show that IDH mutation is associated with diminished levels of TIM-3 cells and fewer interactions between TIM-3 T cells and galectin-9 microglia/macrophages, suggesting reduced activity of the galectin-9/TIM-3 immune checkpoint pathway in IDH-mutant astrocytic gliomas.

Our data confirmed the presence of Th17 cells in expanded T cells from liver metastases. Among CD4 T cell characteristics investigated, TIM-3 but not programmed cell death protein 1 predicted the expansion capacity of TIL while only the Th17 phenotype showed correlation with patients' survival, suggesting a particular role of this T cell subset in CRC immune contexture.

We demonstrated that tPDPNs high subgroup experienced worse overall survival and disease-free survival, and indicated inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy (ACT) in gastric cancer...This study revealed that the abundance of tPDPNs could identify an immunoevasive contexture and might be applied as an independent predictor for poor prognosis and suboptimal ACT responsiveness. Thus, we recommended tPDPNs as a promising therapeutic target in gastric cancer.

Therefore, our results suggest the necessity of evaluating the tumor tissue expression of co-inhibitory molecules and targeting co-expressed molecules in immunotherapies for ESCC patients.

Lastly, Tim-3 downregulated tight junction-associated molecules zona occludens (ZO)-2, ZO-1 and occludin, which may further facilitate tumor progression. Tim-3 plays an oncogenic role in breast cancer and may represent a potential target for antitumor therapy.

High levels of CD8 TIC expressing PD-1 but not TIM-3 and LAG-3 and ERVE4 expression predicted response to nivo (but not to evero) in mccRCC patients. Combination of the IF biomarker with TC PD-L1 improved its predictive value, confirming our previous findings.

Profiling multiple immune and cancer markers on cancer samples with multi-parametric flow cytometry allowed us to obtain protein expression information at the single cell level. Clustering analysis of the proteomic data revealed a signature driven by checkpoint marker expression on CD103CD4 T cells that could potentially be predictive of CTCs and targets of therapy.

In conclusion, the effect and mechanism of miR-122 on high glucose-induced ARPE-19 cells were demonstrated for the first time. miR-122 promoted diabetic retinopathy through targeting TIMP3, making miR-122 a promising target for diabetic retinopathy therapy.

In conclusion, TIM-3-mediated interaction between bmT and leukemia cells is shown as a strong risk factor for relapse in pediatric B-lineage ALL. CD200/TIM-3-signaling, rather than PD-1/PD-L1, is uncovered as a mechanism of T cell dysfunction in ALL with major implication for future immunotherapies.

To the best of our knowledge, this is the first study to identify a novel molecular subtype based on 5mC regulators. The identification of the 5mC-associated subtype may help reveal the potential relation between 5mC and immunity and provide novel insights for the development of individualized therapy for HCC.

Analysis of tumor tissue samples from patients with non-small-cell lung cancer showed negative correlations between CD147 expression on CD8 TILs and the abundance of CD8 TILs, histological grade of the tumor tissue samples, and survival of patients with advanced tumors. Altogether, we found a novel function of CD147 as a negative regulator of antitumor responses mediated by CD8 TILs and identified CD147 as a potential target for cancer immunotherapy.

However, higher TNFRSF9 signature was correlated with larger tumor size shrinkage (p = .003) and better progression-free survival (p = .012) in patients treated with nivolumab but not everolimus. TNFRSF9 CD8 T cells, which possessed both exhaustion and effector phenotype, were identified as an adverse prognosticator in ccRCC. These cells enrichment was associated with better immunotherapy response which indicated these cells potentially be crucial in immunotherapy.

Overall, these findings provide the genetic status of the Tim-3 ligand in DLBCL. Patients with Tim-3 TILs and exhausted Tim-3 CD8 T cells exhibited inferior survival, thus highlighting the possibility of potential therapeutic applications of the inhibition of Tim-3 alone or in combination with other immune checkpoints for treatment of patients with DLBCL.

Histone 3 lysine 9 trimethylation was downregulated and histone 3 lysine 4 trimethylation was upregulated in PD-L1 and TOX2 promoters in tumor tissues, suggesting that PD-L1 and TOX2 upregulation in CRC tumors could be mediated by activating histone 3 lysine 4 trimethylation. Epigenetic modifications in promoters of immune checkpoint and T cell exhaustion genes could induce their upregulation, and potentially implicate the use of epigenetic modifiers to enhance antitumor immunity in CRC patients.

We also found that CD4CTLA-4 T cells in circulation are increased in patients with advanced disease stage. This study simultaneously provides important insights into the differential levels of CD4 T cell subpopulations and IC expression in CRC TME, compared to periphery and associations with clinicopathologic features, which could be used as potential biomarkers for CRC progression and response to therapy.

In summary, HAND2-AS1 may exert inhibitory effects on cervical cancer cell growth and cervical cancer development through its regulation on the miR-21-5p/TIMP3/VEGFA axis. This highlights that HAND2-AS1 may serve as a potential target for cervical cancer diagnosis and treatment.

To investigate the relative influence of PI3Kd-selective versus dual PI3K-d/g inhibition, we first cultured T cells from CLL patients activated with anti-CD3/CD28 beads across logarithmic dose scales of duvelisib or idelalisib. Following transfer to NOG mice engrafted with a human CLL cell line, Duv-CAR T cells demonstrated greater in vivo expansion (Figure 1H), faster elimination of CLL (data not shown), and improved mouse survival (Figure 1I) in a model of high disease burden OSU-CLL. In summary, dual PI3K-d/g inhibition during CLL patient-derived CAR T-cell manufacturing increased yields of Tscm, naïve, and central memory CD8+ Duv-CAR T cells with greater mitochondrial mass and enhanced efficacy in eliminating CLL in a mouse model.

Study Design and This is a phase Ib, open-label, multicenter, dose-escalation study of sabatolimab + HMA (decitabine [Dec] or azacitidine [Aza]) in patients (pts) with AML or HR-MDS (NCT03066648). Sabatolimab + HMA is well tolerated in pts with AML and HR-MDS and continues to show promising antileukemic activity and emerging durability. These results support TIM-3 as a potential therapeutic target and provide a basis for further development of sabatolimab + HMA in pts with AML or higher-risk MDS. Co-senior authors Uma Borate and Andrew H. Wei contributed equally to the work.

Peripheral blood samples were collected at diagnosis(pre) and following completion of treatment (post) from newly diagnosed high risk classical HL patients ages ≥2 to 22 years enrolled on a Children’s Oncology Group sponsored Phase 3 clinical trial AHOD1331 randomizing to therapy containing the anti-CD30 immunoconjugate Brentuximab(Bv-AVEPC) vs. standard chemotherapy (ABVE-PC) (NCT02166463)... T cell responses to tumor associated antigens can be detected in patients with HL at diagnosis and after treatment. Increased T cell responses to MAGE4 and PRAME post therapy suggests that recovery post anti-HL treatment can promote tumor antigen specific T cell immunity in vivo. Further, reduced IL-13 and increased Interferon-γ following treatment suggest a favorable milieu for T cell expansion.

Overall, our findings provided an important addition to the genetic information of Tim-3 ligand in DLBCL. And we uncovered that patients with Tim-3+ TILs and exhausted Tim-3+ CD8+ T cells exhibited inferior survival, supporting potential strategies to block Tim-3 alone or in combination with other immune checkpoints as treatment options for DLBCL patients.

The second most important system is GAL9-TIM3, effecting predominantly NK cells, while T cell are less affected. Thus, the data obtained justify the trials of dual blockade with anti-PD-1 and anti-TIM3 agents in high-risk MDS.

Furthermore, IFNgKO CAR T cells co-cultured with tumor cells and macrophages demonstrated less exhaustion as shown by reduced expression of PD1, Tim3 and Lag3 and increased IFNgKO CAR-T expansion. Conclusions Collectively, these data suggest that IFNg is not required for the efficacy of CAR-T in hematologic malignancies and can potentially be targeted to reduce toxicity and enhance CAR-T efficacy and persistence in the clinic.

Furthermore, IFNgKO CAR T cells co-cultured with tumor cells and macrophages demonstrated less exhaustion as shown by reduced expression of PD1, Tim3 and Lag3 and increased IFNgKO CAR-T expansion. Conclusions Collectively, these data suggest that IFNg is not required for the efficacy of CAR-T in hematologic malignancies and can potentially be targeted to reduce toxicity and enhance CAR-T efficacy and persistence in the clinic.

Furthermore, this TIM-3/Gal-9 “autocrine stimulatory loop” is involved in development of LSCs from preleukemic status, including myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN); frequencies of TIM-3+ cells progressively increased and accumulate driver mutations along with disease progression from early/chronic phase to overt leukemia. Thus, signaling molecules downstream of TIM-3 as well as surface TIM-3 itself might be good target to regulate transformation from preleukemic status.

We also reported that the protein level of TIM-3 in mononuclear cells of ALL patients was 3.2-fold in BM and two-fold in PB more than normals. In conclusion, this study shows that TIM-3 increases in ALL patients, thus the expression of TIM-3 in tumor cells may be considered as a potential predictive factor in ALL patients, which needs to be explored in future.

Altogether, our findings indicate that NLRP3 inflammasome promotes immunosuppression by modulating PD-L1 and immune cells. Accordingly, this study highlights the prognostic and therapeutic values of the NLRP3 inflammasome in lymphoma.

Rechallenge experiments demonstrated immune memory in the long-term responders that led to reject tumour re-implantation, confirming that TIM-3 aptamer treatment in combination with RT elicits specific antitumor immunity in mouse glioma models. These results suggest that immuno-therapies approaches in combination with radiotherapy would be worth to explore in the treatment of deadly DMG-H3K27-Mutant tumours.

In addition, following exposure to tumor CM, IFN-gamma production was lower in T cells co-cultured with TIM-3-defective glia than with normal glia. Collectively, these findings suggest that glial TIM-3 actively and distinctively responds to brain tumor, and plays specific intracellular and intercellular immunoregulatory roles that might be different from TIM-3 on T cells in the brain tumor microenvironment.

Our findings showed that TIM-3 was expressed by CD4, CD8 and regulatory T cells in breast TDLNs, and that expression on CD4 and CD8 T cells was mostly associated with poor prognosticators such as a higher number of involved lymph nodes or higher tumor grade. More studies are required to confirm TIM-3 as a prognostic marker and a target for immunotherapy in breast cancer.

We profiled the immune status of MGMT promoter methylation in GBM and established a local immune signature for GBM that could independently identify patients with a favorable prognosis, indicating a relationship between prognosis and GBM immune signature. MGMT promoter methylation with lower Tim-3 expression was significantly associated with better survival.

The improved tumor regression and survival was dependent on the NKTR-262 driven expansion of NK cells. A clinical trial of BEMPEG/NKTR-262 for patients with metastatic solid tumors is in progress (NCT03435640).

Interestingly, CD137 (4-1BB), a marker of potentially tumor-reactive cells, is expressed predominantly in PD-1+ memory CD8 T cells, with the most intense expression levels observed in the PD-1+/LAG-3+ subset. Conclusions The present results provide insight into the relative (co)expression of potentially targetable immunological pathways, and suggest a biological basis for informing approaches to combination checkpoint inhibition therapy.

Interestingly, CD137 (4-1BB), a marker of potentially tumor-reactive cells, is expressed predominantly in PD-1+ memory CD8 T cells, with the most intense expression levels observed in the PD-1+/LAG-3+ subset. Conclusions The present results provide insight into the relative (co)expression of potentially targetable immunological pathways, and suggest a biological basis for informing approaches to combination checkpoint inhibition therapy.

The improved tumor regression and survival was dependent on the NKTR-262 driven expansion of NK cells. A clinical trial of BEMPEG/NKTR-262 for patients with metastatic solid tumors is in progress (NCT03435640).

Additionally, Tim-3 decreased tight junction (TJ) formation and the transepithelial resistance of endothelial cells by decreasing the expression levels of TJ protein 2, Occludin and claudin 1. In conclusion, these findings suggested that Tim-3 may exert a positive role in angiogenesis and a negative role in TJ formation in vascular endothelial cells, which may provide novel strategies for the treatment of Tim-3 associated diseases.

Using the currently largest TMA cohort of this rare cancer, we delineated the CIR expression profiles in MTC, and identified TIM-3, CTLA-4 expression and PD-1/PD-L1 coexpression as promising biomarkers for tumor recurrence. Furthermore, a subset of advanced MTCs are probably immunogenic, for whom single or combined immunotherapy including TIM-3, PD-1, PD-L1 or CTLA-4 blockade may be potential therapeutic approaches in the future.

Clinically, increased collagen, LAIR1, and TIM-3 expression in melanoma patients treated with PD-1 blockade predict poorer survival and response. Our study identifies collagen and LAIR1 as potential markers for immunotherapy resistance and validates multiple promising therapeutic combinations.

In patients with DLBCL, NOS, those with PD-1 and TIM-3 co-expression as well as those with TIM-3 and BTLA co-expression have poor PFS phase. Patients with PD-1, TIM-3 and LAG-3 co-expression and patients with PD-1, TIM-3, LAG-3 and BTLA co-expression have poor PFS and OS phase.