Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital & Institute, Beijing, China.
BMC Med. 2021 Jul 21;19(1):154. doi: 10.1186/s12916-021-02031-3.
Immune checkpoint inhibitor (ICI) therapy elicits durable antitumor responses in patients with many types of cancer. Genomic mutations may be used to predict the clinical benefits of ICI therapy. NOTCH homolog-4 (NOTCH4) is frequently mutated in several cancer types, but its role in immunotherapy is still unclear. Our study is the first to study the association between NOTCH4 mutation and the response to ICI therapy.
We tested the predictive value of NOTCH4 mutation in the discovery cohort, which included non-small cell lung cancer, melanoma, head and neck squamous cell carcinoma, esophagogastric cancer, and bladder cancer patients, and validated it in the validation cohort, which included non-small cell lung cancer, melanoma, renal cell carcinoma, colorectal cancer, esophagogastric cancer, glioma, bladder cancer, head and neck cancer, cancer of unknown primary, and breast cancer patients. Then, the relationships between NOTCH4 mutation and intrinsic and extrinsic immune response mechanisms were studied with multiomics data.
We collected an ICI-treated cohort (n = 662) and found that patients with NOTCH4 mutation had better clinical benefits in terms of objective response rate (ORR: 42.9% vs 25.9%, P = 0.007), durable clinical benefit (DCB: 54.0% vs 38.1%, P = 0.021), progression-free survival (PFS, hazard ratio [HR] = 0.558, P < 0.001), and overall survival (OS, HR = 0.568, P = 0.006). In addition, we validated the prognostic value of NOTCH4 mutation in an independent ICI-treated cohort (n = 1423). Based on multiomics data, we found that NOTCH4 mutation is significantly associated with enhanced immunogenicity, including a high tumor mutational burden, the expression of costimulatory molecules, and activation of the antigen-processing machinery, and NOTCH4 mutation positively correlates activated antitumor immunity, including infiltration of diverse immune cells and various immune marker sets.
Our findings indicated that NOTCH4 mutation serves as a novel biomarker correlated with a better response to ICI therapy.
免疫检查点抑制剂（ICI）治疗在多种癌症患者中引发持久的抗肿瘤反应。基因组突变可用于预测 ICI 治疗的临床获益。NOTCH 同源物-4（NOTCH4）在几种癌症类型中经常发生突变，但它在免疫治疗中的作用尚不清楚。我们的研究首次研究了 NOTCH4 突变与 ICI 治疗反应之间的关系。
我们在包含非小细胞肺癌、黑色素瘤、头颈部鳞状细胞癌、胃食管癌和膀胱癌患者的发现队列中测试了 NOTCH4 突变的预测价值，并在包含非小细胞肺癌、黑色素瘤、肾细胞癌、结直肠癌、胃食管癌、神经胶质瘤、膀胱癌、头颈部癌、不明原发癌和乳腺癌患者的验证队列中验证了它。然后，我们使用多组学数据研究了 NOTCH4 突变与内在和外在免疫反应机制之间的关系。
我们收集了一个接受 ICI 治疗的队列（n=662），发现 NOTCH4 突变的患者在客观缓解率（ORR：42.9%对 25.9%，P=0.007）、持久临床获益（DCB：54.0%对 38.1%，P=0.021）、无进展生存期（PFS，风险比[HR]=0.558，P<0.001）和总生存期（OS，HR=0.568，P=0.006）方面具有更好的临床获益。此外，我们在一个独立的接受 ICI 治疗的队列（n=1423）中验证了 NOTCH4 突变的预后价值。基于多组学数据，我们发现 NOTCH4 突变与增强的免疫原性显著相关，包括高肿瘤突变负担、共刺激分子的表达和抗原处理机制的激活，并且 NOTCH4 突变与激活的抗肿瘤免疫呈正相关，包括多种免疫细胞的浸润和各种免疫标志物集。
我们的研究结果表明，NOTCH4 突变是一种与 ICI 治疗反应更好相关的新型生物标志物。
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