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.

免疫检查点抑制剂 (ICI) 疗法在肺腺癌 (LUAD) 患者中显示出显着的临床益处。基因组突变可能适用于预测对 ICI 的反应。Eph 受体 A5 (EPHA5) 在乳腺癌、肺癌和其他肿瘤中经常发生突变；然而，它与接受免疫治疗的患者的结果之间的关系仍然未知。在这项研究中，我们报告 EPHA5 突变与 LUAD 中肿瘤突变负荷 (TMB)、新抗原负荷、免疫相关基因表达特征水平和肿瘤浸润淋巴细胞 (TIL) 增加有关。免疫治疗队列中具有 EPHA5 突变的 LUAD 患者比具有野生型 EPHA5 的患者获得了更长的无进展生存期 (PFS) 时间。免疫反应途径是 EPHA5 突变样本中最丰富的途径之一。此外，具有 EPHA5 突变的患者往往对某些靶向分子抑制剂更敏感，包括 serdemetan、lox2 和 PF1-1。总的来说，我们的研究结果表明，鉴定 EPHA5 基因中的突变可以深入了解全基因组的突变负担，并可以作为预测 LUAD 患者免疫反应的生物标志物。