LAG3 is an independent prognostic biomarker and potential target for immune checkpoint inhibitors in malignant pleural mesothelioma: a retrospective study

Our plain-English summary of LAG3 is an independent prognostic biomarker and potential target for immune checkpoint inhibitors in malignant pleural mesothelioma: a retrospective study, by K. Arimura, K. Hiroshima, Y. Nagashima, et al (BMC Cancer, 2023).

The study

• Authors: K. Arimura, K. Hiroshima, Y. Nagashima, T. Nakazawa, A. Ogihara, M. Orimo, Y. Sato, H. Katsura, M. Kanzaki, M. Kondo, E. Tagaya
• Journal: BMC Cancer
• Published: 2023;23(1):1206
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Lymphocyte-activation gene 3 (LAG3) is an immune checkpoint receptor; novel LAG3 immune checkpoint inhibitors (ICIs) exhibit therapeutic activity in melanoma. The role of LAG3and ICIs of LAG3 are unknown in malignant pleural mesothelioma (MPM). This study aimed to uncover the prognostic landscape of LAG3 in multiple cancers and investigate the potential of using LAG3 as an ICIs target in patients with MPM.

Methods: We used The Cancer Genome Atlas (TCGA) cohort for assessing mRNA expression and our cohort for immunohistochemical expression. TCGA cohort were analyzed using the Wilcoxon rank-sum test to compare mRNA expression between normal and tumor tissues in multiple cancers. We used 86 MPM cases from TCGA and 38 MPM cases from our cohort to analyze the expression of LAG3 in tumor-infiltrating lymphocytes. The mean LAG3 mRNA expression was set as the cut-off and samples were classified as positive/negative for immunohistochemical expression. Overall survival (OS) of patients with MPM was determined using the Kaplan-Meier method based on LAG3 mRNA and immunohistochemical expression. OS analysis was performed using the multivariate Cox proportional hazards model. The correlation of LAG3 expression and mRNA expression of tumor immune infiltration cells (TIICs) gene markers were estimated using Spearman correlation. To identify factors affecting the correlation of LAG3 mRNA expression, a multivariate linear regression model was performed.

Results: LAG3 mRNA was associated with prognosis in multiple cancers. Elevated LAG3 mRNA expression was correlated with a better prognosis in MPM. LAG3 expression was detected immunohistochemically in the membrane of infiltrating lymphocytes in MPM. LAG3 immunohistochemical expression was correlated with a better prognosis in MPM. The multivariate Cox proportional hazards model revealed that elevated LAG3 immunohistochemical expression indicated a better prognosis. In addition, LAG3 mRNA expression was correlated with the expression of various gene markers of TIICs, the most relevant to programmed cell death 1 (PD-1) with the multivariate linear regression model in MPM.

Conclusions: 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.

Trial Registration: This study was registered with UMIN000049240 (registration day: August 19, 2022) and approved by the Institutional Review Board (approval date: August 22, 2022; approval number: 2022-0048) at Tokyo Women's Medical University.

© 2023. The Author(s).

In plain English

This retrospective study examined LAG3, an "immune checkpoint" molecule on immune cells, in malignant pleural mesothelioma (MPM). The authors used gene-activity (mRNA) data on 86 MPM patients from The Cancer Genome Atlas (TCGA), a public database. They also stained tumor samples from 38 MPM patients at two Tokyo Women's Medical University hospitals (2000 to 2020); one sample could not be read. The study did not examine asbestos exposure. LAG3 was found on immune cells inside the tumors, not on mesothelioma cells; 10 of 37 samples (27.0%) were LAG3-positive. In the stained samples, LAG3 positivity was linked to longer overall survival after adjusting for age, sex and stage (hazard ratio 0.2255, 95% CI 0.0610–0.8337). In the TCGA patients, high LAG3 mRNA was linked to longer survival in an unadjusted analysis (hazard ratio 0.5820, 95% CI 0.3678–0.9211, P = 0.0178). After adjustment, this mRNA result (0.8779, 95% CI 0.7643–1.0050, P = 0.0592) was not statistically significant. In a regression model, LAG3 mRNA was most closely related to PD-1 gene (PDCD1) activity. The authors concluded that LAG3 is an independent prognostic biomarker and a potential drug target in MPM. They noted that the study was retrospective and small.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective study combining analysis of a public gene-expression database (TCGA) with immunohistochemical staining of tumor samples from the authors' own hospital cohort
• Who was studied: 86 MPM patients from The Cancer Genome Atlas (mRNA data), and 38 MPM patients whose surgical or biopsy samples were obtained at Tokyo Women's Medical University Hospital and Tokyo Women's Medical University Yachiyo Medical Center from March 9, 2000, to June 12, 2020. One sample was excluded as uninterpretable, leaving 37. The TCGA pan-cancer data covering 36 cancer types were also analyzed.
• Exposure: Asbestos exposure was not assessed. The factor studied was LAG3 expression, measured as mRNA in TCGA data (high vs low, cut-off at the mean of 7.390) and by immunohistochemistry in the hospital cohort (positive if 1% or more of lymphocytes stained). Its relation to survival and to immune-cell gene markers was examined.
• Main results:
  • In the hospital cohort, LAG3 was detected on the membrane of tumor-infiltrating lymphocytes but not in mesothelioma cells.
  • Hospital cohort: 10 of 37 MPM cases (27.0%; 8 males, 2 females) were positive for LAG3.
  • Unadjusted survival analysis: high LAG3 mRNA (TCGA, 86 patients) and LAG3-positive immunohistochemistry (hospital cohort) were each associated with better overall survival. mRNA: HR = 0.5820, 95% CI 0.3678–0.9211, P = 0.0178. Immunohistochemistry: HR = 0.4291, 95% CI 0.2043–0.9012, P = 0.0476.
  • After adjusting for age, sex and stage, LAG3-positive immunohistochemistry in the hospital cohort was associated with better overall survival (HR = 0.2255, 95% CI 0.0610–0.8337, P = 0.0197).
  • After adjusting for age, sex and stage, high LAG3 mRNA in the TCGA patients showed only a tendency toward better overall survival (HR = 0.8779, 95% CI 0.7643–1.0050, P = 0.0592). The authors set statistical significance at P less than 0.05.
  • In TCGA MPM data, LAG3 mRNA was correlated with 25 of 37 immune-cell gene markers. In a multivariate linear regression adjusted for 8 markers, it was related to PDCD1 (PD-1) (beta = 0.4915, 95% CI 0.1926 to 0.7905, P = 0.0016) and to CD38.
• The authors' conclusion: The authors concluded that LAG3 is an independent prognostic biomarker in MPM and a potential target for immune checkpoint inhibitors. They suggested that LAG3 and PD-1 inhibitors could contribute to better prognosis, and that combination therapy should be tested.
• Limitations the authors state:
  • The authors stated that the study was retrospective with a small number of patients, and that prospective randomized trials with large populations are needed.
  • The authors stated that the mRNA and immunohistochemistry data came from two different databases, which differed in sex and stage composition, so a study using one identical database is needed.
  • The authors stated that the study was based on clinical research only, and that in vivo and in vitro studies are needed to clarify LAG3's role in MPM.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Biomarker, checkpoint inhibitors, Pleural Mesothelioma, Tumor-Infiltrating Lymphocytes, Overall Survival, Prognosis.

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