Genetic variants of LRRC8C, OAS2, and CCL25 in the T cell exhaustion-related genes are associated with non-small cell lung cancer survival

Front Immunol. 2024 Oct 2:15:1455927. doi: 10.3389/fimmu.2024.1455927. eCollection 2024.

Abstract

Background: T cell exhaustion is a state in which T cells become dysfunctional and is associated with a decreased efficacy of immune checkpoint inhibitors. Lung cancer has the highest mortality among all cancers. However, the roles of genetic variants of the T cell exhaustion-related genes in the prognosis of non-small cell lung cancer (NSCLC) patients has not been reported.

Methods: We conducted a two-stage multivariable Cox proportional hazards regression analysis with two previous genome-wide association study (GWAS) datasets to explore associations between genetic variants in the T cell exhaustion-related genes and survival of NSCLC patients. We also performed expression quantitative trait loci analysis for functional validation of the identified variants.

Results: Of all the 52,103 single nucleotide polymorphisms (SNPs) in 672 T cell exhaustion-related genes, 1,721 SNPs were found to be associated with overall survival (OS) of 1185 NSCLC patients of the discovery GWAS dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, and 125 of these 1,721 SNPs remained significant after validation in an additional independent replication GWAS dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. In multivariable stepwise Cox model analysis, three independent SNPs (i.e., LRRC8C rs10493829 T>C, OAS2 rs2239193 A>G, and CCL25 rs3136651 T>A) remained significantly associated with OS with hazards ratios (HRs) of 0.86 (95% confidence interval (CI) = 0.77-0.96, P = 0.008), 1.48 (95% CI = 1.18-1.85, P < 0.0001) and 0.78 (95% CI = 0.66-0.91, P = 0.002), respectively. Further combined analysis for these three SNPs suggested that an unfavorable genotype score was associated with a poor OS and disease-specific survival. Expression quantitative trait loci analysis suggested that the LRRC8C rs10493829 C allele was associated with elevated LRRC8C mRNA expression levels in normal lymphoblastoid cells, lung tissue, and whole blood.

Conclusion: Our findings suggested that these functional SNPs in the T cell exhaustion-related genes may be prognostic predictors for survival of NSCLC patients, possibly via a mechanism of modulating corresponding gene expression.

Keywords: T cell exhaustion; immunotherapy; non-small cell lung cancer; prognosis; single-nucleotide polymorphism.

MeSH terms

  • 2',5'-Oligoadenylate Synthetase / genetics
  • Aged
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / immunology
  • Carcinoma, Non-Small-Cell Lung* / mortality
  • Chemokines, CC / genetics
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Humans
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / immunology
  • Lung Neoplasms* / mortality
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Prognosis
  • Quantitative Trait Loci*
  • T-Cell Exhaustion
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism

Substances

  • 2',5'-Oligoadenylate Synthetase
  • Chemokines, CC

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Programme Development Grants (Award number(s): 2R01 ES011740, 1R01CA 131274, U01CA209414, CA092824, CA074386, CA090578). Qingyi Wei was supported by NIH grants 2R01 ES011740 and 1R01CA 131274 and also partly supported by the Duke Cancer Institute as part of the P30 Cancer Center Support Grant (Grant ID: NIH/NCI CA014236). The Harvard Lung Cancer Susceptibility Study was supported by NIH grants U01CA209414, CA092824, CA074386 and CA090578 to David C. Christiani. Guojun Lu was supported by Jiangsu Health International Exchange Program.