EPHB1 mutation predicts survival from treatment with immune checkpoint inhibitors and correlated with higher TMB and immune infiltrates in mCRC.

Abstract

e15559 Background: Colorectal cancer has become a common gastrointestinal tumor. Immune checkpoint inhibitors (ICIs) including pembrolizumab, nivolumab, ipilimumab have shown durable responses and have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients, the research exploring the association between gene mutation and clinical benefit is limited. Studies have shown that EPHB1 mutation in the NK cell-related pathway involved in the anti-cancer immune response and associated with survival of NSCLC patients, suggested that EPHB1 may be related to immune microenvironment and tumor immunity. However, the association between EPHB1 mutation and TMB or survival in metastatic Colorectal Cancer (mCRC) is unknown. Methods: Genomic and survival data of mCRC patients administrated with ICIs was retrieved from publicly accessible data(Pancancer.Samstein2018.NGS.1661),the association between EPHB1 mutation and overall survival(OS) was analyzed using Kaplan-Meier curves and log-rank tests. At the same time，the association between EPHB1 mutation and TMB was also analyzed in this public immunotherapy-treated cohort, Wilcoxon test was used for the comparison of TMB. In addition, genome and immune cell infiltration data of 149 patients with Colon Adenocarcinoma (COAD) was obtained from The Cancer Genome Atlas (TCGA). The correlation analysis between immune cell infiltration and EPHB1 mutation status was further analyzed by CIBERSORT-ABS. Statistical significance was set at p = 0.05. Results: 7.3%(8/109) patients in the clinical cohort harbored EPHB1 mutation. Survival analysis in the public cohort demonstrated that EPHB1 mutation resulted in significantly longer OS (14 vs 8 months; HR, 0; p = 0.03) in mCRC patients treated with ICIs. Moreover, EPHB1 mutation was associated with higher TMB in public cohort (p = 0.0004). Furthermore, the correlation analysis between immune infiltration and EPHB1 mutation status in mCRC showed that CD8+T cells, activated memorial CD4+T Cell, M1 macrophages increased significantly in EPHB1 mutation patients(p = 0.023, p = 0.0079, p = 0.034). Conclusions: EPHB1 mutation may serve as a potential positive biomarker of ICIs in mCRC since it relatively correlated with higher TMB. In addition, the up regulation of CD8+T cells, activated Memorial CD4+T Cell as well as the M1 macrophages may be a potential mechanism for the better efficacy of ICIs in patients with EPHB1 mutation.