Zhang Yuchen, Yang Chen, Xu Yanchao, Jiang Xiang, Shi Jiajun, Li Binghua, Yu Decai
State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
Biomol Biomed. 2025 Apr 26;25(6):1314-1321. doi: 10.17305/bb.2024.11069.
Immune checkpoint inhibitors produce durable antitumor effects in various cancers, but not all patients respond. High tumor mutational burden (TMB) is a known predictor of clinical benefit. In this study, we focused on the MHC-I-dependent neoantigen presentation pathway to enhance predictive capabilities beyond TMB. Using pan-cancer immunogenomic analyses of somatic mutation data from The Cancer Genome Atlas (TCGA) and The International Cancer Genome Consortium (ICGC), we analyzed 33 cancer types. Objective response rates (ORRs) to PD-1/PD-L1 inhibitors were evaluated in relation to immune characteristics, including TMB, neoantigen load, MHC-I gene expression, and CD8+ T cell fraction. Spearman's rank correlation was used to assess these relationships. TMB showed the strongest correlation with ORR (r = 0.783, P = 2.17 × 10⁻⁵). However, integrating TMB, HLA-A expression, and CD8+ T cell fraction significantly improved predictive accuracy (r = 0.865, P = 1.80 × 10⁻⁶). Validation in external cohorts confirmed these findings, revealing notable differences in MHC-I pathway activity between responders and non-responders to immunotherapy. Our results demonstrate that the MHC-I antigen presentation pathway is strongly associated with response to PD-1/PD-L1 inhibitors. Importantly, combining antigen expression, processing, presentation, and recognition features provides superior predictive power compared to TMB alone. This integrated approach could improve treatment outcome predictions and advance personalized immunotherapy strategies.
免疫检查点抑制剂在多种癌症中产生持久的抗肿瘤作用，但并非所有患者都有反应。高肿瘤突变负荷（TMB）是已知的临床获益预测指标。在本研究中，我们聚焦于MHC-I依赖的新抗原呈递途径，以增强超越TMB的预测能力。通过对来自癌症基因组图谱（TCGA）和国际癌症基因组联盟（ICGC）的体细胞突变数据进行泛癌免疫基因组分析，我们分析了33种癌症类型。评估了PD-1/PD-L1抑制剂的客观缓解率（ORR）与包括TMB、新抗原负荷、MHC-I基因表达和CD8+ T细胞分数在内的免疫特征的关系。使用Spearman等级相关性来评估这些关系。TMB与ORR的相关性最强（r = 0.783，P = 2.17×10⁻⁵）。然而，将TMB、HLA-A表达和CD8+ T细胞分数整合起来可显著提高预测准确性（r = 0.865，P = 1.80×10⁻⁶）。在外部队列中的验证证实了这些发现，揭示了免疫治疗应答者和非应答者之间MHC-I途径活性的显著差异。我们的结果表明，MHC-I抗原呈递途径与对PD-1/PD-L1抑制剂的反应密切相关。重要的是，与单独的TMB相比，结合抗原表达、加工、呈递和识别特征具有更强的预测能力。这种综合方法可以改善治疗结果预测并推进个性化免疫治疗策略。
