Zhang Zhimin, Gu Yanyan, Su Xiaona, Bai Jing, Guan Wei, Ma Jungang, Luo Jia, He Juan, Zhang Bicheng, Geng Mingying, Xia Xuefeng, Guan Yanfang, Shen Cheng, Chen Chuan
Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Nutrition, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Front Oncol. 2021 Apr 22;11:659321. doi: 10.3389/fonc.2021.659321. eCollection 2021.
Although immune checkpoint inhibitors (ICIs) have shown remarkable benefit for treatment of advanced non-small lung cancer (NSCLC), only a minority of patients can achieve durable responses and the most patients produce an ultra-rapid progressive disease. Here, we collected the availably published datasets and mined the determinants of response to immunotherapy on pathway levels. One hundred six NSCLC patients treated with immunotherapy were combined from Rizvi et al. and Hellman et al. studies (whole exon sequencing). Two independent validation datasets consisted of the MSKCC cohort (targeted sequencing) and data by Anagnostou and colleagues (whole exon sequencing). The Cancer Genome Atlas (TCGA) somatic mutation and gene expression data were applied to explore the immunobiology features. In the first combined cohort, we detected NOTCH pathway altered in 71% patients with durable clinical benefit (DCB) while only 36% among no durable benefit (NDB) (p = 0.005). Compared to NDB group, co-occurrence of NOTCH and at least two DDR (co-DDR) pathway was discovered in DCB group and contributed to a prolonged progression-free survival (PFS) [22.1 3.6 months, p < 0.0001, HR, 0.34, 95% confidence interval (CI), 0.2-0.59]. In two independent datasets, co-occurrence of NOTCH+/co-DDR+ was also validated to be a better immunotherapy efficacy [Cohort 2: 13 6 months, p = 0.034, HR, 0.55, 95% CI, 0.31-0.96; Cohort 3: 21 11 months, p = 0.067, HR, 0.45, 95% CI, 0.18-1.1]. By analyzing TCGA cohort, we found patients with coexisting NOTCH+/co-DDR+ pathway had a higher TMB, more infiltration of CD4+T cells. Overall, co-occurrence of NOTCH and co-DDR pathway reflect a better immunotherapy efficacy in advanced NSCLC. This genomic predictor show promise in stratifying patients that suit for immunotherapy for future clinical practice.
尽管免疫检查点抑制剂（ICI）已显示出对晚期非小细胞肺癌（NSCLC）治疗的显著益处，但只有少数患者能实现持久缓解，而大多数患者会出现超快速进展性疾病。在此，我们收集了已发表的可用数据集，并在通路水平上挖掘免疫治疗反应的决定因素。将Rizvi等人和Hellman等人研究（全外显子测序）中接受免疫治疗的106例NSCLC患者合并。两个独立的验证数据集包括MSKCC队列（靶向测序）以及Anagnostou及其同事的数据（全外显子测序）。应用癌症基因组图谱（TCGA）的体细胞突变和基因表达数据来探索免疫生物学特征。在第一个合并队列中，我们检测到71%具有持久临床获益（DCB）的患者NOTCH通路发生改变，而在无持久获益（NDB）的患者中这一比例仅为36%（p = 0.005）。与NDB组相比，DCB组中发现NOTCH与至少两条DDR（共DDR）通路同时出现，并导致无进展生存期（PFS）延长[22.1±3.6个月，p < 0.0001，风险比（HR），0.34，95%置信区间（CI），0.2 - 0.59]。在两个独立数据集中，NOTCH+/共DDR+同时出现也被验证具有更好的免疫治疗疗效[队列2：13±6个月，p = 0.034，HR，0.55，95% CI，0.31 - 0.96；队列3：21±11个月，p = 0.067，HR，0.45，95% CI，0.18 - 1.1]。通过分析TCGA队列，我们发现同时存在NOTCH+/共DDR+通路的患者肿瘤突变负荷（TMB）更高，CD4+T细胞浸润更多。总体而言，NOTCH与共DDR通路同时出现反映了晚期NSCLC中更好的免疫治疗疗效。这种基因组预测指标在为未来临床实践中适合免疫治疗的患者分层方面显示出前景。
