EPHA5 mutation predicts the durable clinical benefit of immune checkpoint inhibitors in patients with lung adenocarcinoma.

Weimei Huang,Anqi Lin,Linlang Guo,Ting Wei,Weiliang Zhu,Jian Zhang,Peng Luo,Yuchen Liu,Wentao Xu,Qingwen Lyu

doi:10.1038/s41417-020-0207-6

Weimei Huang, Anqi Lin + Show 8 more

Open Access

https://doi.org/10.1038/s41417-020-0207-6

Copy DOI

Abstract

Immune checkpoint inhibitor (ICI) therapy has shown remarkable clinical benefit in lung adenocarcinoma (LUAD) patients. Genomic mutations may be applicable to predict the response to ICIs. Eph receptor A5 (EPHA5) is frequently mutated in breast cancer, lung cancer, and other tumors; however, its association with outcome in patients who receive immunotherapy remains unknown. In this study, we report that EPHA5 mutations were associated with increased tumor mutation burden (TMB), neoantigen load, levels of immune-related gene expression signatures, and enhanced tumor-infiltrating lymphocytes (TILs) in LUAD. LUAD patients with EPHA5 mutations in the immunotherapy cohort achieved a longer progression-free survival (PFS) time than patients with wild-type EPHA5. Immune response pathways were among the top enriched pathways in samples with EPHA5 mutations. In addition, patients with EPHA5 mutations tended to be more sensitive to certain targeted molecular inhibitors, including serdemetan, lox2, and PF1-1. Collectively, our results suggest that identifying mutations in the EPHA5 gene may provide insight into the genome-wide mutational burden and may serve as a biomarker to predict the immune response of patients with LUAD.

Highlights

Immune checkpoint inhibitor (ICI ) therapy has shown remarkable clinical benefit in lung adenocarcinoma (LUAD) patients
The gene mutation pattern showed that Eph receptor A5 (EPHA5) was one of the top 20 frequently mutated genes in patients who achieved durable clinical benefit (DCB) compared to patients who achieved no durable benefit (NDB)
EPHA5 mutation showed a positive correlation with the mutation frequency of several common mutations found in LUAD, such as missense mutations in TP53, KEAP1 and LRP1B, which affect the efficacy of immunotherapies, suggesting that EPHA5 mutations may be related to the response to ICIs in patients with LUAD

Summary

Introduction

Immune checkpoint inhibitor (ICI ) therapy has shown remarkable clinical benefit in lung adenocarcinoma (LUAD) patients. Genomic mutations may be applicable to predict the response to ICIs. Eph receptor A5 (EPHA5) is frequently mutated in breast cancer, lung cancer and other tumors; its association with outcome in patients who receive immunotherapy remains unknown. New selective treatments are urgently needed to improve the outcome of patients with advanced LUAD. Immune checkpoint inhibitors (ICIs), including anti-PD-(L) monotherapy and anti-cytotoxic T cell lymphocyte-4 (anti-CTLA-4), have emerged as therapeutic landscape for patients with advanced cancers, including LUAD [5,6,7,8]. The mechanisms underlying variations in the response to ICIs among LUAD patients are still unclear, and potential biomarkers that are predictive of the benefit of ICIs are needed to elucidate the mechanisms of resistance in ICI nonresponders

Methods

Results

Discussion

Conclusion