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Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer.

ABSTRACT: Somatic mutations together with immunoediting drive extensive heterogeneity within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the T cell antigen receptor (TCR) repertoire. The number of TCR sequences selectively expanded in tumors varies within and between tumors and correlates with the number of nonsynonymous mutations. Expanded TCRs can be subdivided into TCRs found in all tumor regions (ubiquitous) and those present in a subset of regions (regional). The number of ubiquitous and regional TCRs correlates with the number of ubiquitous and regional nonsynonymous mutations, respectively. Expanded TCRs form part of clusters of TCRs of similar sequence, suggestive of a spatially constrained antigen-driven process. CD8+ tumor-infiltrating lymphocytes harboring ubiquitous TCRs display a dysfunctional tissue-resident phenotype. Ubiquitous TCRs are preferentially detected in the blood at the time of tumor resection as compared to routine follow-up. These findings highlight a noninvasive method to identify and track relevant tumor-reactive TCRs for use in adoptive T cell immunotherapy.

SUBMITTER: Joshi K

PROVIDER: S-EPMC6890490 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer.

Joshi Kroopa K de Massy Marc Robert MR Ismail Mazlina M Reading James L JL Uddin Imran I Woolston Annemarie A Hatipoglu Emine E Oakes Theres T Rosenthal Rachel R Peacock Thomas T Ronel Tahel T Noursadeghi Mahdad M Turati Virginia V Furness Andrew J S AJS Georgiou Andrew A Wong Yien Ning Sophia YNS Ben Aissa Assma A Sunderland Mariana Werner MW Jamal-Hanjani Mariam M Veeriah Selvaraju S Birkbak Nicolai J NJ Wilson Gareth A GA Hiley Crispin T CT Ghorani Ehsan E Guerra-Assunção José Afonso JA Herrero Javier J Enver Tariq T Hadrup Sine R SR Hackshaw Allan A Peggs Karl S KS McGranahan Nicholas N Swanton Charles C Quezada Sergio A SA Chain Benny B

Nature medicine 20191007 10

Somatic mutations together with immunoediting drive extensive heterogeneity within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the T cell antigen receptor (TCR) repertoire. The number of TCR sequences selectively expanded in tumors varies within and between tumors and correlates with the number of nonsynonymous mutations. Expanded TCRs can be subdivided into TCRs found in all tumor regions (ubiquitous) and those present in a subset of regions (regional). The number of ...[more]

PMID: 31591606

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Project description:BackgroundHomologous recombination deficiency (HRD) is a well-known biomarker which could predict poly-ADP ribose polymerase 1 (PARP) inhibitor and platinum drug response. As an aggressive cancer, small-cell lung cancer (SCLC) is sensitive to platinum drugs, but relapse occurs rapidly. Herein, we aim to illustrate the genomic alteration patterns of homologous recombination repair (HRR)-related genes in a Chinese SCLC cohort and further analyze the relationship among HRR gene mutations and known biomarkers of immune checkpoint inhibitor (ICI) response, including tumor mutation burden (TMB) and programmed cell death-ligand 1 (PD-L1) expression.MethodsNext-generation sequencing (NGS)-based target capture sequencing of 543 cancer-related genes was performed to analyze the genomic profiles of 133 Chinese SCLC patients, and TMB was calculated. PD-L1 expression was evaluated in 90 out of 133 patients using the SP142 PD-L1 immunohistochemistry assay.ResultsAmong the 133 patients with SCLC, 47 (35.3%) had HRR gene mutations. ATM (8.3%) was the most frequently mutated HRR gene in the cohort, followed by NBN (4.5%). Pathogenic somatic and germline mutations of HRR genes were identified in 11 (23.4%) and 4 (8.5%) patients, respectively. HRR gene mutations cooccurred with KMT2D gene mutations. There were several differences in genomic alterations between patients with HRR gene mutations (HRR-Mut) and without HRR mutations (HRR-WT). The results revealed that TP53 and RB1 were commonly mutated genes in both groups. Mutations in the KMT2D gene and genes in the RTK-RAS pathway occurred more frequently in the HRR-Mut group. Furthermore, we found that mutations in HRR genes were associated with high TMB (Wilcoxon, p = 0.048), but there was no correlation of HRR gene mutation status with PD-L1 expression.ConclusionsWe exhaustively describe the genomic alteration profile of Chinese SCLC patients and provide further evidence that HRR gene mutations are prevalent in SCLC patients.

Dataset Information

Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer.

Publications

Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer.

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