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Abstract：
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.
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.
摘要：
免疫检查点抑制剂(ICI)疗法在患有多种类型癌症的患者中引起持久的抗肿瘤应答。基因组突变可用于预测ICI治疗的临床益处。NOTCH同源物4（NOTCH4）在几种癌症类型中经常发生突变，但其在免疫治疗中的作用尚不清楚。我们的研究是第一个研究NOTCH4突变与ICI治疗反应之间的关联。
我们在发现队列中测试了NOTCH4突变的预测价值，其中包括非小细胞肺癌，黑色素瘤，头颈部鳞状细胞癌,食管胃癌,膀胱癌患者，并在验证队列中验证了它，其中包括非小细胞肺癌，黑色素瘤，肾细胞癌，结直肠癌,食管胃癌,神经胶质瘤,膀胱癌,头颈癌,未知的原发性癌症，和乳腺癌患者。然后，利用多组学数据研究了NOTCH4突变与内在和外在免疫应答机制之间的关系.
我们收集了ICI治疗的队列（n=662），发现NOTCH4突变患者在客观缓解率方面具有更好的临床益处（ORR：42.9%vs25.9%，P=0.007),持久的临床获益（DCB：54.0%vs38.1%，P=0.021),无进展生存期（PFS，危险比[HR]=0.558，P<0.001)，和总体生存率(OS，HR=0.568,P=0.006)。此外,我们在一个独立的ICI治疗队列中验证了NOTCH4突变的预后价值(n=1423).基于多组学数据，我们发现NOTCH4突变与免疫原性增强显著相关,包括高肿瘤突变负担，共刺激分子的表达，和抗原加工机制的激活，和NOTCH4突变与激活的抗肿瘤免疫呈正相关，包括多种免疫细胞和各种免疫标记物的浸润。
我们的研究结果表明，NOTCH4突变是一种新的生物标志物，与ICI治疗更好的反应相关。
我们在发现队列中测试了NOTCH4突变的预测价值，其中包括非小细胞肺癌，黑色素瘤，头颈部鳞状细胞癌,食管胃癌,膀胱癌患者，并在验证队列中验证了它，其中包括非小细胞肺癌，黑色素瘤，肾细胞癌，结直肠癌,食管胃癌,神经胶质瘤,膀胱癌,头颈癌,未知的原发性癌症，和乳腺癌患者。然后，利用多组学数据研究了NOTCH4突变与内在和外在免疫应答机制之间的关系.
我们收集了ICI治疗的队列（n=662），发现NOTCH4突变患者在客观缓解率方面具有更好的临床益处（ORR：42.9%vs25.9%，P=0.007),持久的临床获益（DCB：54.0%vs38.1%，P=0.021),无进展生存期（PFS，危险比[HR]=0.558，P<0.001)，和总体生存率(OS，HR=0.568,P=0.006)。此外,我们在一个独立的ICI治疗队列中验证了NOTCH4突变的预后价值(n=1423).基于多组学数据，我们发现NOTCH4突变与免疫原性增强显著相关,包括高肿瘤突变负担，共刺激分子的表达，和抗原加工机制的激活，和NOTCH4突变与激活的抗肿瘤免疫呈正相关，包括多种免疫细胞和各种免疫标记物的浸润。
我们的研究结果表明，NOTCH4突变是一种新的生物标志物，与ICI治疗更好的反应相关。
