Purpose: NOTCH signaling is associated with tumorigenesis, mutagenesis, and immune tolerance in non–small cell lung cancer (NSCLC), indicating its association with the clinical benefit of immune checkpoint inhibitors (ICI). We hypothesized that NOTCH mutation in NSCLC might be a robust predictor of immunotherapeutic efficacy. Experimental Design: Multiple-dimensional data including genomic, transcriptomic, and clinical data from cohorts of NSCLC internal and public cohorts involving immunotherapeutic patients were analyzed. Polymorphism Phenotyping v2 (PolyPhen-2) system was performed to determine deleterious NOTCH mutation (del- NOTCH mut). Further investigation on molecular mechanism was performed in The Cancer Genome Atlas (TCGA) data via CIBERSORT and gene set enrichment analysis. Results: Our 3DMed cohort ( n = 58) and other four cohorts (Rizvi, POPLAR/OAK, Van Allen, and MSKCC; n = 1,499) uncovered marked correlation between NOTCH1/2/3 mutation and better ICI outcomes in EGFR/ALK WT population, including objective response rate (2.20-fold, P = 0.001), progression-free survival [HR, 0.61; 95% confidence interval (CI), 0.46–0.81; P = 0.001], and overall survival (HR, 0.56; 95% CI, 0.32–0.96; P = 0.035). Del- NOTCH mut exhibited better predictive function than non-deleterious NOTCH mutation, potentially via greater transcription of genes related to DNA damage response and immune activation. Del- NOTCH mut was not linked with prognosis in TCGA cohorts and chemotherapeutic response, but was independently associated with immunotherapeutic benefit, delineating the predictive, but not prognostic, utility of del- NOTCH mut. Conclusions: This work distinguishes del- NOTCH mut as a potential predictor to favorable ICI response in NSCLC, highlighting the importance of genomic profiling in immunotherapy. More importantly, our results unravel a possibility of personalized combination immunotherapy as adding NOTCH inhibitor to ICI regimen in NSCLC, for the optimization of ICI treatment in clinical practice.

中文翻译：

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鉴定有害的 NOTCH 突变作为非小细胞肺癌有效免疫治疗的新预测因子。

目的：NOTCH 信号与非小细胞肺癌 (NSCLC) 的肿瘤发生、诱变和免疫耐受相关，表明其与免疫检查点抑制剂 (ICI) 的临床益处相关。我们假设 NSCLC 中的 NOTCH 突变可能是免疫治疗疗效的有力预测因素。实验设计：分析了多维数据，包括来自免疫治疗患者的 NSCLC 内部和公共队列的基因组、转录组和临床数据。执行多态性表型 v2 (PolyPhen-2) 系统以确定有害的 NOTCH 突变 (del-NOTCH mut)。通过 CIBERSORT 和基因集富集分析在癌症基因组图谱 (TCGA) 数据中对分子机制进行了进一步研究。结果：我们的 3DMed 队列（n = 58）和其他四个队列（Rizvi、POPLAR/OAK、Van Allen 和 MSKCC；n = 1,499）发现了 NOTCH1/2/3 突变与 EGFR/ALK WT 人群中更好的 ICI 结果之间的显着相关性，包括客观缓解率（2.20 倍，P = 0.001）、无进展生存期 [HR，0.61；95% 置信区间 (CI)，0.46–0.81；P = 0.001] 和总生存期（HR，0.56；95% CI，0.32–0.96；P = 0.035）。Del-NOTCH mut 表现出比非有害 NOTCH 突变更好的预测功能，这可能是通过与 DNA 损伤反应和免疫激活相关的基因的更大转录来实现的。Del-NOTCH mut 与 TCGA 队列中的预后和化疗反应无关，但与免疫治疗益处独立相关，描述了 del-NOTCH mut 的预测效用，而非预后效用。结论：这项工作将 del-NOTCH mut 区分为 NSCLC 中有利 ICI 反应的潜在预测因子，突出了基因组分析在免疫治疗中的重要性。更重要的是，我们的结果揭示了个性化联合免疫治疗的可能性，即在 NSCLC 的 ICI 方案中添加 NOTCH 抑制剂，以优化临床实践中的 ICI 治疗。