LAG3 elevation

LAG3 demonstrates strong associations within tumor immunity, participating in a range of immune and inflammatory signaling pathways. Elevated levels of LAG3 are linked not only to T cell exhaustion but also to increased immune infiltration and polarization towards M1 macrophages.

We also examined the distribution of LAG3 at the single-cell level and explored its functional significance. A comprehensive and systematic analysis of LAG3 would facilitate a comprehensive evaluation of LAG3 in cancer biology and provide valuable insights for cancer management.

LAG3 expression was correlated with prognosis in multiple cancers, particularly MPM; LAG3 is an independent prognostic biomarker of MPM. LAG3 regulates cancer immunity and is a potential target for ICIs therapy. PD-1 and LAG3 inhibitors may contribute to a better prognosis in MPM.

Reconstitution of ATM and inhibition of XBP1 or EGR2 in PCa T cells suppressed LAG3 expression and restored the effector function of CD4 T cells from PCa. Our study revealed the mechanism of LAG3 upregulation in CD4 T lymphocytes of PCa patients and may provide insights for the development of immunotherapeutic strategies for PCa treatment.

Ex vivo biodistribution data revealed increased LAG-3 expression and nanobody uptake in MM-infiltrating organs. Using flow cytometry, a high expression of LAG-3 was observed in MM cells and lymphoid cells, which significantly increased within BM-derived CD8+ T-cells at end-stage of disease. Altogether, these data illustrate increased expression of LAG-3 upon disease progression and fosters the evaluation of LAG-3 blocking therapies, particularly in the context of immunotherapeutic approaches in MM.

Conclusions GBM with high expression of PD1, CTLA4 and LAG3 display frequent mutations in the ERBB-PI3K signaling pathway including EGFR and PTEN. These genes correlated with presence of gamma-delta T cells in tumor infiltrates.

Serum-derived LAG-3 was identified out of a diverse array of chemokine and cytokines as the immune-based factor most significantly associated with improved HGSOC survival. These findings suggest that LAG-3 could be implemented as a non-invasive patient predictive marker for improved HGSOC clinical outcomes.

Our findings suggest that higher levels of LAG3 in UM with histopathologically high-risk parameters predict high metastatic potential and that it could be used as a targeted immunotherapy alone or in combination with PD-1/PD-L1 blockade agents.

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.

Patients with posttreatment high levels of sLAG3 and LAG3+ cells in PB showed poor prognosis of AGC patients after the nivolumab therapy, suggesting that these are useful predictive biomarkers. LAG3 may be a promising target in immunotherapy for AGC. Clinical trial information: UMIN000032686.

Since the genomic alterations of only BAP1 was associated with the PD-1 therapy response signature and higher LAG3 and VISTA gene expression, it might be a candidate marker for immune checkpoint blockade therapy. Our results on the impact of TSG genotypes on MPM and the correlations between TSG alterations and molecular pathways provide a foundation for developing individualized MPM therapies.

These checkpoints thus represent attractive therapeutic targets, and indeed the LAG3 inhibitor relatlimab was recently approved for the treatment of metastatic melanoma in combination with anti-PD-1 therapy...We further saw that the prognostic value of LAG3 levels varies depending on the tissue site queried (i.e., primary tumor versus metastases), and that relatively higher LAG3 levels at metastatic sites may predict a better response to immunotherapy and longer overall survival after the development of metastatic disease. These findings may have important implications for the design of future studies involving LAG3 or other immunotherapies in RCC.

LAG-3 expression had an independent impact on MFS. In addition to PD-1 and PD-L1, further immune checkpoints, such as LAG-3, could serve as therapeutic targets in breast cancer.

Combined detecton of sTIL and LAG-3 may be more useful in gastric cancer than using either alone. Age, tumor size, Lauren classification and postoperative adjuvant chemotherapy are independent prognostic factors for patients with advanced gastric adenocarcinoma.

We observed heterogeneity in the immune profile of the real-world HR+ and TN tumors in this cohort. A subset of tumors in both subtypes expressed markers or signatures previously reported to be associated with response to ICB.

Immune checkpoint inhibitors (ICIs), such as pembrolizumab and atezolizumab, in combination with chemotherapy have prolonged survival outcomes in mBC with triple negative subtype. And the prognostic significance of LAG3 expression was different between CK+ cells and CK- cells. These findings need to be proved in large scale clinical trials.

Conclusions These exploratory analyses support the hypothesis that NIVO+RELA enhances immune activation compared with NIVO alone, and that LAG-3 may be a promising biomarker of tumor inflammation. Although LAG-3 alone may not be a useful predictive biomarker for selection of patients with melanoma for NIVO+RELA vs NIVO regimens, further work is required to assess the clinical utility of LAG-3, likely as part of a composite biomarker of immunotherapy susceptibility.

In brief, our results indicated the important role of m6 methylation in affecting the tumor immune microenvironment and the survival of patients with LUAD. The m6A methylation gene signatures might serve as promising therapeutic targets and help the immunotherapy of LUAD in the future.

High expression of LAG-3 is associated with angiogenesis and poor prognosis in HCC patients. With the deepening of research, LAG-3 is likely to become a novel biomarker for clinical diagnosis and prognosis and can even be a therapeutic target of HCC.

In addition, HRAS Q61 was found to be correlated with worse prognosis in pts treated with pembro (HR = 2.779, 95% CI [1.04-7.423], p =0.03) but not G12 or G13, and displayed the highest MPAS score (p = 0.05), which had previously been demonstrated to indicate immune evasion...HRAS mt SCC also showed an immune-cold TME associated with high MAPK pathway activation and high LAG3 expression. This warrants further investigation, in particular in HRAS Q61 or HRAS mt SCC, with combination therapies targeting MAPK pathway or LAG3 protein.

Resected colonic carcinomas with high expression of PD-L1 and LAG3 proteins on immune cells were associated with improved prognosis in colon carcinoma. The mechanism underlying the improved prognosis of colon carcinomas bearing high numbers of immunoregulatory cells needs further investigation.

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.

IMP321 and relatlimab are promising monoclonal antibodies targeting LAG3 in melanoma. Finally, high FGL1 and LAG3 expression induces EGFR-TKI and gefitinib resistance, and anti-PD-1 therapy resistance, respectively. We present a comprehensive overview of the role of LAG3/FGL1 in cancer, suggesting novel anti-tumor therapy strategies.

Inhibitory immune checkpoint receptors are aberrantly expressed in the peripheral blood of cHL and DLBCL patients in which high LAG-3 in DLBCL patients and PD-1/LAG-3 in cHL patients are associated with relapse occurrence and worse prognosis, respectively.

These features are accompanied by comparable levels of PD-L1 protein expression compared with primary lung tumors. These results highlight unique aspects of the tumor immune microenvironment within the brain and provide further support for intracranially focused therapies.

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.

In an exploratory analysis of pretreatment samples from advanced non-small-cell lung carcinoma patients treated with pembrolizumab, high CD8 was predictive of improved overall and progression-free survival, while high LAG-3, but not high LAG-3/CD8 index, was associated with improved progression-free survival. In conclusion, the clinicopathologic correlations and prognostic impact of LAG-3 in non-small-cell lung carcinoma are histotype-dependent, highlighting differences in the immune microenvironment between adenocarcinomas and squamous-cell carcinomas. The predictive impact of LAG-3 warrants further investigation.

Resected  colonic   carcinoma s with high  expression of  PD-L1 and LAG3  proteins  on immune cells  were  associated with  improved  prognosis  in  colon carcinoma. The mechanism underlying  the improved  prognosis  of colon  carcinomas bearing high numbers of immunoregulatory cells needs further investigation. 

This study demonstrated that LAG3 is an important immune checkpoint that is closely associated with PD-1/PD-L1. LAG3 may be a promising novel immunotherapy target for SCLC.

Furthermore, in 50 patients who underwent TACE, the serum LAG-3 level was significantly decreased at 3 day after TACE. Both pre-TACE and post-TACE serum LAG-3 levels could serve as powerful predictors for tumor response of TACE, and high pre-TACE serum LAG-3 level was an indicator for poor prognosis in HCC.

LAG-3+ and LAG3+CD8+ cell proportion added predictive value to CD38+ cells for predicting survival outcome in immunotherapy-treated HCC. LAG-3 may be used in conjunction with CD38 to predict responsiveness to ICB in HCC.

Higher LAG-3 and PD-1 on TILs, and higher PD-L1 expression on TCs, and pathological type III were identified as independent risk factors for poorer DFS in NPC patients. Our data demonstrate that LAG-3 is a promising inhibitory receptor that may play an important role in anti-NPC therapy.

As other immune checkpoint inhibitors have transformed the management of difficult to treat cancers, such as melanoma, it is hoped that LAG-3 might have the same potential. This review will explore LAG-3 modulation as an anticancer therapy, highlighting recent clinical developments.