Checkpoint inhibitors (CPIs) augment adaptive immunity. Systematic pan-tumor analyses may reveal the relative importance of tumor-cell-intrinsic and microenvironmental features underpinning CPI sensitization. Here, we collated whole-exome and transcriptomic data for >1,000 CPI-treated patients across seven tumor types, utilizing standardized bioinformatics workflows and clinical outcome criteria to validate multivariable predictors of CPI sensitization. Clonal tumor mutation burden (TMB) was the strongest predictor of CPI response, followed by total TMB and CXCL9 expression. Subclonal TMB, somatic copy alteration burden, and histocompatibility leukocyte antigen (HLA) evolutionary divergence failed to attain pan-cancer significance. Dinucleotide variants were identified as a source of immunogenic epitopes associated with radical amino acid substitutions and enhanced peptide hydrophobicity/immunogenicity. Copy-number analysis revealed two additional determinants of CPI outcome supported by prior functional evidence: 9q34 (TRAF2) loss associated with response and CCND1 amplification associated with resistance. Finally, single-cell RNA sequencing (RNA-seq) of clonal neoantigen-reactive CD8 tumor-infiltrating lymphocytes (TILs), combined with bulk RNA-seq analysis of CPI-responding tumors, identified CCR5 and CXCL13 as T-cell-intrinsic markers of CPI sensitivity.

检查点抑制剂 (CPI) 增强适应性免疫。系统性泛肿瘤分析可能揭示支撑 CPI 致敏的肿瘤细胞内在特征和微环境特征的相对重要性。在这里，我们整理了超过 1,000 名接受 CPI 治疗的七种肿瘤类型患者的全外显子组和转录组数据，利用标准化生物信息学工作流程和临床结果标准来验证 CPI 致敏的多变量预测因子。克隆肿瘤突变负荷 (TMB) 是 CPI 反应的最强预测因子，其次是总 TMB 和CXCL9表达。亚克隆 TMB、体细胞拷贝改变负担和组织相容性白细胞抗原 (HLA) 进化分歧未能达到泛癌意义。二核苷酸变体被鉴定为与自由基氨基酸取代和增强的肽疏水性/免疫原性相关的免疫原性表位的来源。拷贝数分析揭示了先前功能证据支持的 CPI 结果的另外两个决定因素：与反应相关的 9q34 ( TRAF2 ) 丢失和与耐药性相关的CCND1扩增。最后，对克隆性新抗原反应性 CD8 肿瘤浸润淋巴细胞 (TIL) 进行单细胞 RNA 测序 (RNA-seq)，结合对 CPI 反应肿瘤的批量 RNA-seq 分析，将CCR5和CXCL13确定为 T 细胞内在标记物CPI 敏感性。