LAG3 expression

These results reinforce clinical data on the expected benefit of ICI in metastatic pRCC treatment, as PD-L1 expression is a factor of poor prognosis in this multicenter cohort.

In addition, we found that the frequency of cytotoxic ILCs and NKp46+ILC3 in tumors positively correlates with monocytic cells and conventional type 2 dendritic cells, revealing potentially new interconnected immune cell subsets in the tumor microenvironment. Consequently, these observations may have direct relevance to tumor microenvironment composition and how ILC subset may influence anti-tumor immunity.

The BET inhibitor IBET151, combined with anti-CTLA-4, overcame innate ICB resistance however, sequential BET inhibition failed against acquired resistance in mouse models...BET proteins in melanoma may play an oncogenic role by inducing immune suppression and driving T cell dysfunction. The study demonstrates an effective combination for innately unresponsive melanoma patients to checkpoint inhibitor immunotherapy, yet highlights BET inhibitors' limitations in an acquired resistance context.

In conclusion, the tumor microenvironment of penile squamous cell carcinoma seems to be affected by both HIV and HPV infections. TIM3 appears to be a potential therapeutic target in PSCC patients with hrHPV infections.

ICIs are worthy of further exploration in these patients. UV signatures and high TMB could be used to help select patients for treatment.

No significant correlation was observed between the sPD-L2 and sLAG-3 levels and PD-L2 and LAG-3 expression via immunohistochemistry. In conclusion, sPD-L2 and sLAG-3 expression may serve as a potential biomarker for predicting IO combination therapy efficacy.

Rituximab combined with CAR-T therapy is effective for improving the long-term prognosis of B-ALL patients who have failed multiple lines of therapy. In vitro, we observed that rituximab potentially improves CAR-T efficacy by sensitizing ALL to CART-mediated cytotoxicity and reducing CAR-T exhaustion.

The mechanistic study reveals LAGE3 is required for the VEGFA mRNA stability. This research may open new avenues for diagnosis and targeted therapy in HCC.

In ICI-ILD, we found an increase in CD57+ CD8+ T cells expressing immune checkpoints (TIGIT+ LAG3+ TIM-3+ PD-1+), FCRL5+ B cells, and CCR2+ CCR5+ CD14+ monocytes. These findings uncover the diverse immunophenotypes and possible pathomechanisms of cancer treatment-related pneumonitis.

: In summary, this comprehensive study defines specialized CD8+ T-cell subpopulations in cirrhosis, with CXCL13+ Tex cells displaying an exhausted phenotype associated with immune dysregulation and advanced disease. Key genes and pathways regulating these cells present potential therapeutic targets.

A study using multiplex immunohistochemical analysis showed that MMR-deficient colon adenocarcinomas are characterized by more pronounced immune infiltration and increased expression of immune checkpoints in microenvironmental cells, mainly in the area of invasive tumor growth. The data obtained may be important for understanding the mechanisms of immune-mediated control of tumor growth and the choice of immunotherapy tactics depending on MMR status.

Tumor-promoting genes such as CD163 and CD209 were highly expressed in the myeloid cells, and depletion marker genes such as TIGIT, LAG3 were highly expressed in NK/T cells. Our study may provide a reference for the molecular mechanism of HNSCC and theoretical basis for the development of new therapeutic strategies.

In this study, a prognostic model was constructed based on 8 PRGs were proved to be independent prognostic factors of OS and associated with tumor immune microenvironment. These 8 prognostic genes were involved in OS development and may serve as new targets for developing therapeutic drugs.

We showed that knockdown of USP7 or treatment with USP7 inhibitor P5091 suppressed liver cancer growth by promoting CD8+ T cell activity in Hepa1-6 xenograft mice and in HepG2 or Huh7 cells co-cultured with T cells, whereas USP7 overexpression produced the opposite effect...In an immunocompetent liver cancer mouse model, the dual blockade of USP7 and LAG3 resulted in a superior antitumor activity compared with anti-LAG3 therapy alone. We conclude that USP7 diminishes CD8+ T cell activity by a USP7/PRDM1 positive feedback loop on FGL1 production in liver cancer; USP7 might be a promising target for liver cancer immunotherapy.

Our proteomic analysis reveals an intra-tumoral population of SMA+CAFs enriched in pure DM. Additionally, increased expressions of immune checkpoints (LAG-3 and PD-1) in LA and within tumor were associated with poorer prognosis. These findings might have therapeutic implications and help guide treatment selection in addition to informing potential prognostic significance.

Our findings provide insights into the safety profile of combined PD-1 and LAG-3 blockade in gastroesophageal cancer and highlight the potential of ctDNA analysis to dynamically assess systemic tumor burden during neoadjuvant ICI that may open a therapeutic window for future intervention. ClinicalTrials.gov registration: NCT03044613 .

In summary, GCs impacted phenotype and function of untransduced and CAR T cell with different magnitude. The nature of the CAR costimulatory domain influenced the magnitude of CAR T cell response to GCs.

More importantly, LFOP combined with radiotherapy significantly improve the T cell infiltration in tumor and elevate systemic antitumor immune response. In conclusion, we developed a novel peptide blocking LAG-3/FGL1 which can restore T cell function, and the bispecific peptide synergizes with radiotherapy to further enhance the antitumor immune response.

A low-to-intermediate positive correlation was observed between PD-L1 and TIM-3 expressions (rho: 0.333, p < 0.01). Although PD-L1 expression was higher in grade 3 NET/NEC, MSI status was prominent in grade 1/2 NET.

This study may provide a new therapeutic approach for CRLM. Further clinical study is needed.

In summary, T cell-tumor cell interactions, such as LAG-3-HLA-II, could confer an immunosuppressive environment in human GBM, leading to poor prognosis in patients. Therefore, targeting the LAG-3-HLA-II interaction could be beneficial in ICI immunotherapy to improve the clinical outcome of GBM patients.

Additionally, PD1 induced increased lymphocyte activating 3 (LAG3) expression in a significant fraction of CD8+ T cells and Treg cells, indicating potential drug resistance and feedback mechanisms. In conclusion, our work provides preclinical data for the Combined immunotherapy of CRC using intratumoral delivery of IFNγ and systemic anti-PD1 monoclonoal antibody.

Altogether, this research revealed that circulating NKT-like cells in CRC patients exhibited suppressive phenotype and functional impairment, which was more pronounced in NKG2A+ NKT-like cells. These findings suggest that NKG2A blockade may restore anti-tumor effector function in NKT-like cells, which provides a potential target for immunotherapy in CRC patients.

P2, N=33, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Sep 2023 --> Jun 2024

The transcriptional repressor B cell lymphoma-6 was partially required for their maintenance. Altogether, we propose that the LAG3+CXCR5+ CD4 T cell subset could play a role in maintaining CD4 T cell responses during persistent infections.

P2, N=132, Recruiting, Shanghai Henlius Biotech | N=60 --> 132

TFH-like cytotoxic CD4+ T cells have high LAG-3/BLIMP1 and low TCF1 expression without self-renewal ability, whereas non-cytotoxic TFH cells express low LAG-3/BLIMP1 and high TCF1 with self-renewal ability, closely resembling the relationship between terminally differentiated and stem-like progenitor exhaustion in CD8+ T cells, respectively. Our findings provide deep insights into TFH-like CD4+ T cell exhaustion with helper progenitor and cytotoxic differentiated functions, mediating anti-tumor immunity orchestrally with CD8+ T cells.

P=N/A, N=128, Recruiting, Samsung Medical Center

Further, LAG-3 expression was found to be increased within the TME following intratumoral CPMV administration. The integration of CPMV IIT with LAG-3 inhibition holds significant potential to improve treatment outcomes by concurrently inducing a comprehensive anti-tumor immune response, enhancing local immune activation, and mitigating T cell exhaustion.

A combined hypoxia and immune-related gene could be a novel predictive model for OS and immunotherapy estimation of BLCA patients and TFRC could be used as a potential therapeutic target in the future.

The role of LAG-3 expression on circulating NK cells, as well as the expression of LAG-3 ligands on tumor cells and the early modulation of circulating cytotoxic CD4+ T cells warrant further investigation as exploitable predictive biomarkers for dual PD-1 and LAG-3 blockade.Trial registration: NCT02460224. Registered 02/06/2015.

Lastly, a correlation analysis between γδ T cell abundance, immune checkpoint gene expression, and clinical outcomes in melanoma patients showed that low expression of immune checkpoint genes, including LAG3, HAVCR2, and PDCD1, was associated with improved 1-year overall survival, emphasizing the significance of these genes in predicting patient outcomes, potentially outweighing the impact of γδ T cell abundance. This study offers critical insights into the dynamic interaction between γδ T cells, immune checkpoint receptors, and melanoma, providing valuable prospectives for potential therapeutic avenues and predictive markers in this intricate interplay.

Taken together, these results suggest that high LAG-3 levels in and of themselves do not predict resistance to anti-PD-1/PD-L1 checkpoint blockade. Even so, since LAG-3 is often co-expressed with PD-1, PD-L1 and/or CTLA-4, selecting patients for combinations of checkpoint blockade based on immunomic co-expression patterns is a strategy that merits exploration.

P2, N=20, Active, not recruiting, Dan Zandberg | Recruiting --> Active, not recruiting

The realization of LAG-3's promise necessitates global collaboration and equal access. Multinational trials are expected to ascertain the efficacy of the intervention in various patient groups.

Co-culture experiments with MC38 and CD8 T cells demonstrated that APS decreased the expression of co-inhibitory receptor LAG3 in CD8 T cells by targeting STAT3/Gal-3 in MC38 cells. Mechanism investigations revealed that APS specifically improved CD8 T cell function through modulation of the STAT3/Gal-3/LAG3 pathway to inhibit CRC development, providing insights for future clinical development of natural anti-tumor drugs and immunotherapies as a novel strategy combined with immune checkpoint inhibitors (ICIs).

In conclusion, our study implies that LAG3 can serve as a potential prognostic biomarker for KIRC. Furthermore, blocking both LAG3 and PDCD1 may alleviate resistance to anti-PDCD1 therapy, providing novel insights for immunotherapy decision-making in KIRC patients.

KEB-SCCs showed the lowest expression of the exhaustion markers TIM-3 and LAG-3 compared with all other groups. These findings identify IDO, PD-1, and PD-L1 to be increased in EB-SCCs and candidate targets for combinatory treatments, especially in DEB-SCCs.

In addition, we will discuss what will be the future implementation of these strategies against cancer drug resistance. Finally, we will emphasize the practical steps to lay the groundwork for enlightened policy for intervention and resource allocation to care for cancer patients.

In conclusion, the CD8sp_41BBz STEAP1 CAR T cells had superior expansion and survival in vitro and in vivo, compared to the IgGsp_CD28z counterpart, and a less exhausted phenotype upon repeated antigen exposure. Such persistence may be important for clinical efficacy.

Grz expression was significantly decreased in CD8T cells incubated with CD138LAG-3 PCs, compared to CD138LAG-3 PCs in patients with plasma cell dyscrasia, n = 31, p = 0.0041. LAG-3 expression on malignant PCs can be involved in the development of MM from MGUS by decreasing the expression of Grz in CD8T cells.

In addition, SKM-BBz CAR-T cells showed upregulation of early memory markers, such as TCF7 and CCR7, as well as downregulation of pro-apoptotic proteins, such as BAK1 and BID, which may be associated with phenotypical and functional differences between SKM-BBz and SKM-28z CAR-T cells. In conclusion, we developed novel SKM9-2-derived CAR-T cells with the 4-1BB costimulatory domain, which could provide a promising therapeutic approach against refractory MM.