PD-1 elevation

OSCC arising in never-smokers/never-drinkers exhibit heightened PD-1/PD-L1 signaling, suggesting potential efficacy of immune checkpoint therapy in this subgroup of tumors.

These findings indicate that elevated PD-1 expression on TILs can be associated with immune evasion during the early stages of malignancy evolution in the NSCLC setting and further research is required to further delineate the role of PD-1/PD-L1 pathway on tumor immune senescence. These results underline the potential role of PD-1/PD-L1 inhibitors in the treatment of early-stage NSCLC.

in AML patients, there is upregulation in PD-1, which indicates that PD-1 is a possible biomarker for AML. PD-1 rs36084323 G/A may have a role in AML risk.

In our cohort, the patients with CLL expressed elevated levels of PD-1 and CTLA-4 immune checkpoints on activated and memory B cell subsets. However, there was no correlation between these immune checkpoint expressions and B2M levels.

Targeting this axis could serve as a potential therapeutic strategy to enhance the clinical outcomes of DLBCL patients. Further studies are necessary to explore the prognostic implications of PD-1 and sPD-L1 expression levels in DLBCL patients.

Our results provide the first evidence that Rab37 small GTPase mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion, and the tumor promoting function of Rab37/PD-1 axis in T cells of TME in lung cancer. The expression profile of Rab37high/PD-1high/TIM3high in tumor-infiltrating CD8+ T cells is a biomarker for poor prognosis in lung cancer patients.

Importantly, patients harboring higher numbers of CD3CD8PD-1 T-cells together with PD-L1CTCs had a survival advantage when receiving front-line immunotherapy. Thus, this study proposes, for first time possible, immune cell-CTCs interaction, as well as a potential novel clinical biomarker for ICI responses in ES-SCLC patients.

Our analysis shows that RRP tissue shows elevated levels of multiple immune check point targets and VEGFR3, with varied patterns unique to each papilloma patient. Some of these immune checkpoint markers already have novel immunotherapies available or in development, providing molecular rationale to offer these systemic treatments to selected patients affected by RRP alongside VEGF inhibitors. Laryngoscope, 2024.

Dysfunctional TILs and imbalanced immune mediators contribute to therapeutic insufficiency, shedding light on local and systemic immune interplay. Our study informs immunological signatures for treatment prediction and CC prognosis.

Elevated PD-1 expression on peripheral T cells is associated with increased risk of HCC progression and shorter time to progression in bridging/downstaging to transplant HCC patients undergoing first-cycle Y. Treatment-induced lymphopenia was not associated with treatment response, or increased progression risk, suggesting this anticipated adverse event does not impact short-term HCC outcomes.

We demonstrated the feasibility of using radiomics to correlate tumor-infiltrating lymphocyte (TIL) distribution (PD1+CD8+ to CD8+ ratio) and tumor-associated macrophage (TAM) quantification (CD60+ to PanCK+ ratio). Validation of the results with a larger sample size and external data is warranted. *Clinical Relevance/Application: We reported the first use of multiphase CT radiomics as an non-invasive method to assess TIL and TAM in ccRCC.

Contrary to the conclusions of prior studies with MSLN-targeted CARs, membrane distal epitopes were superior to membrane proximal epitopes when binders were paired with the correct spacer, and shed MSLN and MUC16 were not inhibitory for the best-performing CARs, regardless of target epitope. Furthermore, regulated expression enhanced the potency and durability of response compared to constitutive expression. This approach may improve CAR activity in patients with MSLN+ solid tumors or leukemia.

This study suggested that in HCC patients, the elevated abundance of MDSCs in the peripheral blood was negatively correlated with the level of apoE in peripheral blood, and the abnormal level of apoE was also associated with elevated levels of PD-1+ and CTLA-4+ T lymphocytes. ApoE2 subtype was a potential protective factor for HCC patient's OS and apoE4 subtype suggested poor prognosis.

In summary, we showed the significance of selected ICI as outcome predictors in AML management. Further, multicentre studies are required for validation of those data.

Conclusion Concurrent use of checkpoint inhibitors along with other treatment modalities is being studied in a variety of solid tumors. Expressions of negative immune regulators like PD-1 and Foxp3 can pave way for a better understanding of the extent of immunosuppression in the glial tumor environment, which is imperative to formulate new therapeutic approaches.

HD/alum/ICG hydrogel with NIR light may have both CD8 T cell-linked immune responses and ICG-related photodynamic/photothermal effects. Additional injection of immune checkpoint inhibitor can ultimately suppress primary and distant tumor growth by combination with those therapeutic actions.

Analysis of a dataset containing 3039 primary breast cancer samples on the R2 Genomics Analysis Platform revealed increased TIM-3, galectin-9 and LAG-3 expression, not only in triple-negative breast cancer but also in the HER2 and hormone receptor-positive breast cancer subtypes. These data indicate that LAG-3 and TIM-3 represent additional key molecules within the breast cancer anti-immunity landscape.

CD36CD8 T cells exhibit impaired immune function and high infiltration of CD36CD8 T cells indicated poor prognosis and inferior chemotherapy response in NSCLC patients. CD36 could be a therapeutic target in combination with chemotherapy in NSCLC patients.

Our research showed that iNOS inhibition with the iNOS inhibitor (1400W) and COX2 inhibitor (Celebrex) diminished HCC tumor growth...We also found that iNOS/COX2 blockade result in more CD4+ T helper cells and CD8+ tumor infiltrating lymphocyte (TIL), but reduce the number of exhausted CD4+ T cells and CD8+ T cells (PD1-high, Lag3+, CD39+ Tex). The results suggesting that iNOS/COX2 inhibitor therapy may alleviate HCC growth by promoting a anti-tumorigenic TME, modifying lymphoid spatial localization and gene expression phenotypes and decreasing T-cell exhaustion.

We conclude that CD8+ TILs with high avidity are more exhausted and less effector like than low avidity CD8+ TILs. This finding has major implications for T cell-based cancer immunotherapy.

Elevated intrinsic T cells with high PD-1 and TIGIT exhaust signatures and attenuated cytotoxicity in TME were associated with the late-stage relapse of CAR T-cell treatment. In summary, the cellular compositions of TME as allies of CAR T cells may contribute to the anti-tumor efficacy at the initial stage, whereas anti-CD19 CAR T-cell disappearance and host response immunosuppression may work together to cause lymphoma relapse after an initial, near-complete elimination phase.

Assessing the relative spatial proximity of PD-1/PD-L1 contributes to a deeper understanding of tumor immune escape and generates prognostic information in locally advanced NSCLC patients.

To systematically discover the determinants of this response, we analyzed single-cell transcriptome data generated from 17 bone marrow samples longitudinally collected from 6 RS patients enrolled in a phase I study of the anti-PD1 drug nivolumab with concurrent ibrutinib (NCT 02420912). We again identified ZNF683 among the top upregulated genes in RS-R (Log2 fold change = 2.13, p=0.037), along with other genes enriched in our ZNF683high CD8 E/EM signature (BATF, CORO1A, CD38, ITGB2, GZMM), while RS-NR were enriched in NK-like genes (KLRC1, FCGR3A, KLRG1, KLRF1 and FCER1G). In conclusion, we identify ZNF683 as marking a CD8 T cell population associated with CPB response in RS blood and bone marrow and provide evidence that this transcription factor regulates key cellular pathways involved in immune anti-tumor response, with implications for understanding CPB response in RS and other malignancies.

In BAL from advanced LC patients, T cells present features of exhaustion. T cells in t-BAL could be the best surrogate of tumor-infiltrating T cell, and future studies should evaluate T cell phenotype and density as potential biomarkers for cancer immunotherapy outcome.

P2; Recruiting --> Active, not recruiting | Trial primary completion date: Jul 2022 --> Dec 2022

Larger and prospective trials are warranted to validate both ICI activity and predictive biomarkers in PLELC. This study was partly presented as a poster at the IASLC 20th World Conference on Lung Cancer 2019, 7-10 September 2019, Barcelona, Spain.

This multidisciplinary clinical study decodes for the first time how obesity, through the OB-R/leptin axis, might activate TILs but apparently dysfunctional as it is not translated into higher pCR; probably due to the presence of exhausted features such as high PD-1 expression. The role of Ob-R together with PD-1 as a potential biomarker for immunotherapy should be further explored.

Conclusion  PD-1 and PD-L1 is expressed in all subgroups of breast carcinoma. Patients in all such groups are amenable to immunotherapy, provided they are found suitable otherwise.

In summary, the iPDX models reproduced key features of the corresponding human tumor. The observed variability and high PD-1 expression are important considerations that need to be addressed in order to develop a reproducible model system.

Abnormal levels of laboratory parameters and intensified tumor burden can be expected if elevated baseline plasma PD-1/PD-L1 levels are found.

In conclusion, we demonstrated the expression status of PVR/TIGIT and PD-L1/PD-1 in LUSC. PVR/PD-L1 co-expression was an independent prognostic factor in LUSC patients and may serve as a potential predictive biomarker for dual-targeting immunotherapy.

The PD-1/PD-L1 may induce immune suppression in OLK and accelerate the progress of malignant transformation.

In short, our study demonstrates that a high increment of PD-1 is associated with superior PFS in advanced-stage melanoma patients treated with nivolumab plus ipilimumab. In contrast, decreasing levels of IFNγ and IL6, and increasing levels of CXCL5 are associated with response to pembrolizumab. These results suggest that using serial samples to monitor changes in cytokine levels early during treatment is informative for treatment response.

Treg PD-1 engages LEC PD-L1 to regulate lymphatic TEM. Treg PD-1 signals through LEC PD-L1 to induce the PI3K/Akt pathway to modulate cell junctions, and through classical NFκB-p65 to regulate VCAM-1 expression. The modulated LEC structures uniquely affect only Treg but not Teff TEM.

Immune cell subpopulations and cancer cell-intrinsic features are associated with different clinical outcomes in BC.

Many clinical trials of LAG3 inhibitors have had modest effects, but recent data suggests that the LAG3 antibody relatlimab together with nivolumab (anti-PD1) provided greater benefit than nivolumab alone in patients with melanoma. High LAG3 was found in almost a quarter of tumor samples and significantly associated with other immune checkpoints with FDA-approved drugs. Ongoing studies combining LAG3 inhibitors and specific immune checkpoint inhibitors may yield more clinical benefit if individualized immunomic transcript interrogation is undertaken, rather than population-based approaches without employment of rationally combined agents matched to each patient’s cancer.

T cell activation score may serve as a candidate for personalized immunotherapy in HGSOC. The application of anti-PD-1 therapy to HGSOC should be cautious.

Our data suggests that both baseline immune profile ‘setpoints’ and dynamic remodeling of immune features, including expansion of exhausted CD8+ T cells, are associated with response to ICIs in patients with mTNBC. Lack of response to ICIs is defined not only by a lack of CD8+ T cell expansion, but also by high levels of circulating ASCs, Tfh, and terminal NK cells at baseline. Additional studies to further explore and validate features of this T cell: B cell: NK cell axis and response to ICIs in patients with mTNBC are ongoing.

Supporting this finding, we observed that increased numbers of CD45RA+ T cells correlated with a favorable survival. These results indicate that the differentiation stage may determine the role of T cells in predicting patient outcome in FL.

Finally, we validated the functionality of these models using checkpoint inhibitors like Ipilimumab (Ipi), Nivolumab (Nivo), Pembrolizumab (Pembro), cell therapies and immune cell engagers.Methods HSC-humanized mice were generated by i.v. transplantation of CD34+stem cells to immunodeficient NOG mice. These models have been employed for preclinical evaluation of novel checkpoint inhibitors, cell therapies and immune cell engagers. Our models allow preclinical, translational studies on tumor immune biology as well as evaluation of new therapies, drug combinations and biomarker identification and validation.

Results showed that anti-PD-1-hIL21 fusion proteins were efficient at inhibiting tumor growth in B-hIL21R and B-hPD-1/hIL21R mice. Altogether, B-hIL21R and B-hPD-1/hIL21R mice are promising humanized mouse models for preclinical in vivo studies to assess novel drug candidates.

In conclusion, BLEACH&STAIN mfIHC in combination with a deep learning-based framework for automated PD-L1 assessment on tumor and immune cells enabled a rapid and comprehensive assessment of PD-L1 expression in different cell types and their interrelation with inflammatory cells. Our approach enabled the identification of six major PD-L1 phenotypes ranging from an PD-L1+ tumor cell inflamed phenotype (G1.1) with a spatial T-cell exclusion to a non-inflamed PD-L1+ immune cell phenotype showing a particular poor prognosis (G2.2) to a non-inflamed PD-L1 negative phenotype (G3.2).