Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 or its ligand (PD-1/L1) have expanded the treatment landscape against cancers but are effective in only a subset of patients. Tumor mutation burden (TMB) is postulated to be a generic determinant of ICI-dependent tumor rejection. Here we describe the association between TMB and survival outcomes among microsatellite-stable cancers in a real-world clinicogenomic cohort consisting of 70,698 patients distributed across 27 histologies. TMB was associated with survival benefit or detriment depending on tissue and treatment context, with eight cancer types demonstrating a specific association between TMB and improved outcomes upon treatment with anti-PD-1/L1 therapies. Survival benefits were noted over a broad range of TMB cutoffs across cancer types, and a dose-dependent relationship between TMB and outcomes was observed in a subset of cancers. These results have implications for the use of cancer-agnostic and universal TMB cutoffs to guide the use of anti-PD-1/L1 therapies, and they underline the importance of tissue context in the development of ICI biomarkers.

针对程序性细胞死亡蛋白 1 或其配体 (PD-1/L1) 的免疫检查点抑制剂 (ICIs) 扩大了癌症治疗范围，但仅对一小部分患者有效。肿瘤突变负荷 (TMB) 被认为是 ICI 依赖性肿瘤排斥的一般决定因素。在这里，我们描述了现实世界临床基因组队列中 TMB 与微卫星稳定癌症生存结果之间的关联，该队列由分布在 27 个组织学的 70,698 名患者组成。 TMB 与生存获益或损害相关，具体取决于组织和治疗背景，八种癌症类型表明 TMB 与抗 PD-1/L1 疗法治疗后改善结果之间存在特定关联。在各种癌症类型中，TMB 截止值范围广泛，可带来生存获益，并且在一部分癌症中观察到 TMB 与结果之间存在剂量依赖性关系。这些结果对于使用癌症不可知和通用 TMB 截止值来指导抗 PD-1/L1 疗法的使用具有影响，并且它们强调了组织背景在 ICI 生物标志物开发中的重要性。