Genetic associations of T cell cancer immune response-related genes with T cell phenotypes and clinical outcomes of early-stage lung cancer
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.Meth...
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e000336.full |
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| author | Xifeng Wu Jianchun Gu Linbo Wang David W Chang Yuanqing Ye Maosheng Huang Jack A Roth Qinchuan Wang |
| author_facet | Xifeng Wu Jianchun Gu Linbo Wang David W Chang Yuanqing Ye Maosheng Huang Jack A Roth Qinchuan Wang |
| author_sort | Xifeng Wu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a8c5ab2cd6ab4a188a9055f497e0529b |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-a8c5ab2cd6ab4a188a9055f497e0529b2024-11-10T21:05:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2019-000336Genetic associations of T cell cancer immune response-related genes with T cell phenotypes and clinical outcomes of early-stage lung cancerXifeng Wu0Jianchun Gu1Linbo Wang2David W Chang3Yuanqing Ye4Maosheng Huang5Jack A Roth6Qinchuan Wang72 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States2 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States1 Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China2 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States3 Department of Epidemiology, Center for Biostatistics, Bioinformatics, and Big Data, Second Affiliated Hospital and Department of Big Data in Health Science, School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China2 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States1 Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA1 0000 0004 1759 700Xgrid.13402.34Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital and Department of Epidemiology and Health Statistics School of Public HealthZhejiang University School of Medicine Zhejiang Hangzhou ChinaBackground 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.https://jitc.bmj.com/content/8/2/e000336.full |
| spellingShingle | Xifeng Wu Jianchun Gu Linbo Wang David W Chang Yuanqing Ye Maosheng Huang Jack A Roth Qinchuan Wang Genetic associations of T cell cancer immune response-related genes with T cell phenotypes and clinical outcomes of early-stage lung cancer Journal for ImmunoTherapy of Cancer |
| title | Genetic associations of T cell cancer immune response-related genes with T cell phenotypes and clinical outcomes of early-stage lung cancer |
| title_full | Genetic associations of T cell cancer immune response-related genes with T cell phenotypes and clinical outcomes of early-stage lung cancer |
| title_fullStr | Genetic associations of T cell cancer immune response-related genes with T cell phenotypes and clinical outcomes of early-stage lung cancer |
| title_full_unstemmed | Genetic associations of T cell cancer immune response-related genes with T cell phenotypes and clinical outcomes of early-stage lung cancer |
| title_short | Genetic associations of T cell cancer immune response-related genes with T cell phenotypes and clinical outcomes of early-stage lung cancer |
| title_sort | genetic associations of t cell cancer immune response related genes with t cell phenotypes and clinical outcomes of early stage lung cancer |
| url | https://jitc.bmj.com/content/8/2/e000336.full |
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