Research Paper Volume 13, Issue 1 pp 598—618

EPHA5 mutations predict survival after immunotherapy in lung adenocarcinoma

Zhiming Chen1, *, , Ji Chen2, *, , Dandan Ren3, *, , Jiao Zhang3, , Ying Yang3, , Henghui Zhang4, , Beibei Mao3, , Haitao Ma1, ,

  • 1 Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
  • 2 Department of Thoracic Surgery, Huashan Hospital, Shanghai, China
  • 3 Genecast Precision Medicine Technology Institute, Beijing, China
  • 4 Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China
* Equal contribution

Received: June 10, 2020       Accepted: October 3, 2020       Published: December 3, 2020
How to Cite

Copyright: © 2020 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Eph receptors constitute the largest family of RTKs, and their associations with antitumor immunity and immunotherapy are largely unknown. By integrating genomic, transcriptomic and clinical data from cohorts in public databases, we identified EPHA5 as the most common mutated gene of Eph receptors in lung adenocarcinoma (LUAD). Moreover, compared with EPHA5 wild-type (WT) patients, EPHA5-mutant (Mut) patients exhibited significantly enhanced infiltration of CD8+ T cells and M1 macrophages, reduced recruitment of immunosuppressive regulatory T cells (Tregs) into the tumor site, as well as the increased level of chemokine, interferon-gamma, inhibitory immune checkpoint signatures, tumor mutation burden (TMB) and tumor neoantigen burden (TNB). Additionally, EPHA5 mutation cooccurred with homologous recombination (HR) or mismatch repair (MMR) gene mutations. These data were validated in the LUAD cell line H1299 and a Chinese LUAD cohort. Most importantly, clinical analysis of a Memorial Sloan Kettering Cancer Center (MSKCC) immunotherapy cohort indicated that LUAD patients with EPHA5 mutations who were treated with immunotherapy had markedly prolonged survival times.

Our results revealed the correlation of EPHA5 mutations with tumor immune microenvironment and predictive factors for immunotherapy, implying the potential of EPHA5 mutations as a prognostic marker for the prognosis of LUAD patients to immune checkpoint blockade therapy.


NSCLC: non-small cell lung cancer; LUAD: lung adenocarcinoma; SCLC: small cell lung cancer; LUSC: lung squamous cell carcinoma; EGFR: epidermal growth factor receptor; ALK: anaplastic lymphoma kinase; IFN-γ: interferon-γ; NF-κB: nuclear factor kappa B; TNF: tumor necrosis factor; RTKs: receptor tyrosine kinases; Tregs: regulatory T cells; MSKCC: Memorial Sloan Kettering Cancer Center; TCGA: The Cancer Genome Atlas; PD-1: programmed death-1; PD-L1: programmed death ligand-1; TMB: tumor mutation burden; TILs: tumor-infiltrating lymphocytes; TNB: tumor neoantigen burden; HR: homologous recombination; MMR: mismatch repair.