Genetic associations of T cell cancer immune response-related genes with T cell phenotypes and clinical outcomes of early-stage lung cancer.

Abstract

BACKGROUND:

Recent advances in T cell-related immunotherapy have brought remarkable progress in the treatment of non-small cell lung cancer (NSCLC). However, whether and how genetic variations of T cell cancer immune response genes can influence clinical outcomes of NSCLC patients remain obscure.

METHODS:

In this multiphase study, we assessed 2450 single-nucleotide polymorphisms (SNPs) from 280 T cell cancer immune response-related genes in 941 early-stage NSCLC patients (discovery n=536; validation n=405) to analyze the variants' associations with outcomes and to observe the effects on T cell phenotypes.

RESULTS:

We found 14 SNPs in 10 genes were associated with NSCLC outcomes (p<0.05) in both phases. Among them, TRB:rs1964986 was the most significant variant associated with recurrence risk after meta-analysis (HR 1.84, 95% CI 1.35 to 2.52, p=1.15E-04), while IDO1:rs10108662 was the most significant SNP associated with death risk (HR 1.87, 95% CI 1.40 to 2.51, p=2.17E-05). Analysis of unfavorable genotypes indicated cumulative effects on death and recurrence risks. Seven treatment-specific variants were found to predict opposite outcomes in surgery-only and surgery-plus-chemotherapy subgroups. Expression quantitative trait loci analysis indicated that six SNPs significantly correlated with their corresponding gene expression. T cells from high-risk subjects displayed reduced degranulation (p=0.02) and decreased cytotoxicity against cancer cells (p<0.01). Gene expression profile indicated increased IDO1 expression and decreased IL2, PRF and GZMB expression in high-risk subjects.

CONCLUSIONS:

Genetic variations in T cell cancer immune response pathways can impact outcomes and may be served as predictors for treatment efficacy in early-stage NSCLC patients. The correlation between immune genotypes and T cell antitumor immunity suggests a biological link between host immune genetics and NSCLC prognosis.

• Authors: Qinchuan Wang, Jianchun Gu, Linbo Wang, David W Chang, Yuanqing Ye, Maosheng Huang, Jack A Roth, Xifeng Wu
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 8 Issue 2 (08 2020) ISSN: 2051-1426 [Electronic] England
• PMID: 32764075 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Topics

• Aged
• Humans
• Lung Neoplasms (genetics, pathology)
• Neoplasm Staging
• Phenotype
• Polymorphism, Single Nucleotide (genetics)
• T-Lymphocytes (metabolism)
• Treatment Outcome