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Cancer Sci. 2018 Dec 24. doi: 10.1111/cas.13919. [Epub ahead of print]

Significant differences in T cell receptor repertoires in lung adenocarcinomas with and without EGFR mutations.

Author information

1
Department of Medicine, The University of Chicago, Chicago, IL, USA.
2
Department of Respiratory Medicine, Tohoku University, Sendai, Japan.
3
Cancer Precision Medicine Centre, Japanese Foundation for Cancer Research, Tokyo, Japan.
4
The Ph.D. Program for Translational Medicine, Taipei Medical University and Academia Sinica, Taipei, Taiwan.
5
Department of Thoracic Surgery, Tohoku University, Sendai, Japan.
6
Department of Pathology, Tohoku University Hospital, Sendai, Japan.
7
Department of Surgery, The University of Chicago, Chicago, IL, USA.

Abstract

Recent clinical trials of non-small cell lung cancer with immune checkpoint inhibitors revealed that patients with EGFR mutations had more unfavorable outcome compared with those with wild-type EGFR. However, the underlying mechanism for the link between EGFR mutations and immune resistance remains unclear. We performed T cell receptor (TCR) repertoire analysis of resected lung adenocarcinoma tissues with/without EGFR mutations to investigate the characteristics of TCR repertoire. We collected a total of 39 paired (normal and tumor) lung tissue samples (20 had EGFR mutations) and conducted TCR repertoire analysis as well as whole-exome sequencing (WES) and transcriptome analysis. TCR diversity index in EGFR-mutant tumors was significantly higher than that in EGFR-wild-type (median [range] 552 [162-1,135] vs. 230 [30-764]; P < 0.01), suggesting higher T cell clonal expansion in EGFR-wild-type tumors than in EGFR-mutant tumors. In WES, EGFR-mutant tumors showed lower numbers of non-synonymous mutations and predicted neoantigens than EGFR-wild-type tumors (P < 0.01, P = 0.03, respectively). The number of non-synonymous mutations revealed a positive correlation with the sum of frequencies of the TCR╬▓ clonotypes of 1% or higher in tumors (r = 0.52, P = 0.04). The present study demonstrates significant differences in TCR repertoires and number of predicted neoantigens between EGFR-mutant and wild-type lung tumors. Our findings provide important information to understand the molecular mechanism that EGFR-mutant patients show unfavorable responses to immune checkpoint inhibitors. This article is protected by copyright. All rights reserved.

KEYWORDS:

EGFR mutation; Lung adenocarcinoma; Neoantigen; Non-synonymous mutation; T cell receptor repertoire

PMID:
30582659
DOI:
10.1111/cas.13919
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