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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.

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


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.


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

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