Significant differences in T cell receptor repertoires in lung adenocarcinomas with and without epidermal growth factor receptor mutations

Abstract

Recent clinical trials of non‐small cell lung cancer with immune checkpoint inhibitors revealed that patients with epidermal growth factor receptor (EGFR) mutations had more unfavorable outcomes 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 and without EGFR mutations to investigate the characteristics of TCR repertoires. 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. The TCR diversity index in EGFR‐mutant tumors was significantly higher than that in EGFR‐wild‐type tumors (median [range] 552 [162‐1,135] vs 230 [30‐764]; P < .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 < .01, P = .03, respectively). The number of non‐synonymous mutations revealed a positive correlation with the sum of frequencies of the TCRβ clonotypes of 1% or higher in tumors (r = .52, P = .04). The present study demonstrates significant differences in TCR repertoires and the number of predicted neoantigens between EGFR‐mutant and wild‐type lung tumors. Our findings provide important information for understanding the molecular mechanism behind EGFR‐mutant patients showing unfavorable responses to immune checkpoint inhibitors.

Association of molecular characteristics with survival in advanced non-small cell lung cancer patients treated with checkpoint inhibitors

“…Despite the heterogeneity of the study population, our findings are consistent with previous reports that patients with PD-L1 ≥50% fare better with ICIs and patients who had EGFR mutations had worse OS than patients who were EGFR negative treated with ICIs [10]. The underline mechanism of lack of benefits in EGFR mutated tumors remains unclear and a recent study of T cell receptor repertoire analysis showed that EGFR-mutated tumors had lower clonal T cell expansion compared with EGFR non-mutated tumors [31]. Our real-world experience with patient populations in different settings from clinical trials validated the role of PD-L1 level ≥50% and EGFR mutations in ICIs.…”

Evaluating the Potential of T Cell Receptor Repertoires in Predicting the Prognosis of Resectable Non-Small Cell Lung Cancers

“… 37 Through whole-exome sequencing of these paired samples, top frequently somatic-mutated genes such as EGFR , TP53 , and TTN , etc., whose mutations were well-known in lung cancer, were further studied with TCR repertoires. Although it has been previously reported that EGFR mutant tumors had a higher TCRβ diversity index than WT tumors, 38 difference of TCR repertoires in tumors with and without EGFR mutation was not observed in our study ( Figures 4 A–4D). Instead, TTN gene somatic mutation was shown to affect the profiling of intratumoral TCR repertoires ( Figures 4 I–4L), this results could be one of reasons of the correlation of TTN mutations with favorable prognosis in lung squamous cell carcinoma.…”

The Promises and Challenges of Tumor Mutation Burden as an Immunotherapy Biomarker: A Perspective from the International Association for the Study of Lung Cancer Pathology Committee

“…96,97 A higher TCR diversity index in EGFR-mutated than EGFR wild-type tumors might suggest a higher Tcell clonal expansion in EGFR wild-type tumors. 98 This could indirectly point to a possible reason for the unfavorable response of EGFR-mutated NSCLC to ICI. However, there are currently no published data on the predictive role of TCR clonality and diversity and their correlation with other biomarkers, including PD-L1 and TMB.…”