Zhang Zhen, Wu Hao-Xiang, Lin Wu-Hao, Wang Zi-Xian, Yang Lu-Ping, Zeng Zhao-Lei, Luo Hui-Yan
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China.
Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, People's Republic of China.
BMC Med. 2021 Feb 2;19(1):26. doi: 10.1186/s12916-020-01899-x.
A critical and challenging process in immunotherapy is to identify cancer patients who could benefit from immune checkpoint inhibitors (ICIs). Exploration of predictive biomarkers could help to maximize the clinical benefits. Eph receptors have been shown to play essential roles in tumor immunity. However, the association between EPH gene mutation and ICI response is lacking.
Clinical data and whole-exome sequencing (WES) data from published studies were collected and consolidated as a discovery cohort to analyze the association between EPH gene mutation and efficacy of ICI therapy. Another independent cohort from Memorial Sloan Kettering Cancer Center (MSKCC) was adopted to validate our findings. The Cancer Genome Atlas (TCGA) cohort was used to perform anti-tumor immunity and pathway enrichment analysis.
Among fourteen EPH genes, EPHA7-mutant (EPHA7-MUT) was enriched in patients responding to ICI therapy (FDR adjusted P < 0.05). In the discovery cohort (n = 386), significant differences were detected between EPHA7-MUT and EPHA7-wildtype (EPHA7-WT) patients regarding objective response rate (ORR, 52.6% vs 29.1%, FDR adjusted P = 0.0357) and durable clinical benefit (DCB, 70.3% vs 42.7%, FDR adjusted P = 0.0200). In the validation cohort (n = 1144), significant overall survival advantage was observed in EPHA7-MUT patients (HR = 0.62 [95% confidence interval, 0.39 to 0.97], multivariable adjusted P = 0.0367), which was independent of tumor mutational burden (TMB) and copy number alteration (CNA). Notably, EPHA7-MUT patients without ICI therapy had significantly worse overall survival in TCGA cohort (HR = 1.33 [95% confidence interval, 1.06 to 1.67], multivariable adjusted P = 0.0139). Further gene set enrichment analysis revealed enhanced anti-tumor immunity in EPHA7-MUT tumor.
EPHA7-MUT successfully predicted better clinical outcomes in ICI-treated patients across multiple cancer types, indicating that EPHA7-MUT could serve as a potential predictive biomarker for immune checkpoint inhibitors.
免疫治疗中的一个关键且具有挑战性的过程是识别能够从免疫检查点抑制剂（ICI）中获益的癌症患者。探索预测性生物标志物有助于最大化临床益处。已表明Eph受体在肿瘤免疫中发挥重要作用。然而，EPH基因突变与ICI反应之间的关联尚缺乏研究。
收集已发表研究中的临床数据和全外显子测序（WES）数据，并整合为一个发现队列，以分析EPH基因突变与ICI治疗疗效之间的关联。采用另一个来自纪念斯隆凯特琳癌症中心（MSKCC）的独立队列来验证我们的发现。使用癌症基因组图谱（TCGA）队列进行抗肿瘤免疫和通路富集分析。
在14个EPH基因中，EPHA7突变型（EPHA7-MUT）在对ICI治疗有反应的患者中富集（FDR校正P<0.05）。在发现队列（n = 386）中，EPHA7-MUT和EPHA7野生型（EPHA7-WT）患者在客观缓解率（ORR，52.6%对29.1%，FDR校正P = 0.0357）和持久临床获益（DCB，70.3%对42.7%，FDR校正P = 0.0200）方面存在显著差异。在验证队列（n = 1144）中，EPHA7-MUT患者观察到显著的总生存优势（HR = 0.62 [95%置信区间，0.39至0.97]，多变量校正P = 0.0367），这与肿瘤突变负荷（TMB）和拷贝数改变（CNA）无关。值得注意的是，在TCGA队列中，未接受ICI治疗的EPHA7-MUT患者总生存显著更差（HR = 1.33 [95%置信区间，1.06至1.67]，多变量校正P = 0.0139）。进一步的基因集富集分析显示EPHA7-MUT肿瘤中的抗肿瘤免疫增强。
EPHA7-MUT成功预测了多种癌症类型中接受ICI治疗患者的更好临床结局，表明EPHA7-MUT可作为免疫检查点抑制剂的潜在预测生物标志物。
