Analysis of PD1, LAG3, TIGIT, and TIM3 expression in human lung adenocarcinoma reveals a 25-gene signature predicting immunotherapy response

Cell Rep Med. 2024 Dec 17;5(12):101831. doi: 10.1016/j.xcrm.2024.101831. Epub 2024 Nov 25.

Abstract

Immune checkpoint inhibitors (ICIs) have advanced the treatment of non-small cell lung cancer (NSCLC). This study evaluates the predictive value of CD8+ T cell exhaustion in patients with lung adenocarcinoma treated with ICIs. By analyzing tumor samples from 166 patients through multiplex immunofluorescence, we quantify tumor-infiltrating lymphocytes (TILs) expressing exhaustion markers programmed cell death-1 (PD1), lymphocyte activation gene 3 (LAG3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and T cell immunoglobulin and mucin domain 3 (TIM3). Their co-expression is associated with ICI resistance, irrespective of programmed cell death ligand-1 (PD-L1) status. We also identify a 25-gene signature indicative of CD8+ T cell exhaustion with high predictive accuracy for ICI response. Validated using several datasets from various clinical trials, this signature accurately predicts ICI responsiveness. Our findings highlight T cell exhaustion's significance in lung adenocarcinoma responses to ICIs and suggest the 25-gene signature as a potential universal biomarker to reinforce precision medicine. This was registered under Clinical Trial registration number NCT02534649.

Keywords: LAG3; PD1; TIGIT; TIM3; biomarkers; exhaustion; immune checkpoint inhibitors; lung adenocarcinoma; tumor microenvironment.

Publication types

  • Clinical Study

MeSH terms

  • Adenocarcinoma of Lung* / drug therapy
  • Adenocarcinoma of Lung* / genetics
  • Adenocarcinoma of Lung* / immunology
  • Adenocarcinoma of Lung* / metabolism
  • Adenocarcinoma of Lung* / pathology
  • Aged
  • Antigens, CD* / genetics
  • Antigens, CD* / metabolism
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Hepatitis A Virus Cellular Receptor 2* / genetics
  • Hepatitis A Virus Cellular Receptor 2* / metabolism
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immunotherapy* / methods
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / immunology
  • Lung Neoplasms* / pathology
  • Lymphocyte Activation Gene 3 Protein*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Male
  • Middle Aged
  • Programmed Cell Death 1 Receptor* / genetics
  • Programmed Cell Death 1 Receptor* / metabolism
  • Receptors, Immunologic* / genetics
  • Receptors, Immunologic* / metabolism
  • T-Cell Exhaustion
  • Transcriptome / genetics

Substances

  • Antigens, CD
  • Biomarkers, Tumor
  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • Immune Checkpoint Inhibitors
  • Lag3 protein, human
  • Lymphocyte Activation Gene 3 Protein
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic
  • TIGIT protein, human

Associated data

  • ClinicalTrials.gov/NCT02534649