PD-1 blockade has transformed the management of advanced clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of the PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors from patients with advanced ccRCC enrolled in prospective clinical trials of treatment with PD-1 blockade by whole-exome and RNA sequencing, integrated with immunofluorescence analysis, to uncover the immunogenomic determinants of the therapeutic response. Although conventional genomic markers (such as tumor mutation burden and neoantigen load) and the degree of CD8⁺ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations associated with response or resistance to PD-1 blockade. These advanced ccRCC tumors were highly CD8⁺ T cell infiltrated, with only 27% having a non-infiltrated phenotype. Our analysis revealed that infiltrated tumors are depleted of favorable PBRM1 mutations and enriched for unfavorable chromosomal losses of 9p21.3, as compared with non-infiltrated tumors, demonstrating how the potential interplay of immunophenotypes with somatic alterations impacts therapeutic efficacy.

PD-1 阻断已经改变了晚期透明细胞肾细胞癌 (ccRCC) 的治疗，但 PD-1 反应的驱动因素和阻力因素仍未完全阐明。在这里，我们通过全外显子组和 RNA 测序，结合免疫荧光分析，分析了参加 PD-1 阻断治疗前瞻性临床试验的 592 例晚期 ccRCC 患者的肿瘤，以揭示治疗反应的免疫基因组决定因素。^{尽管常规基因组标记（例如肿瘤突变负荷和新抗原负荷）和 CD8 +} T 细胞浸润程度与临床反应无关，但我们发现许多染色体改变与 PD-1 阻断的反应或耐药相关。这些晚期 ccRCC 肿瘤高度 CD8 ⁺T 细胞浸润，只有 27% 具有非浸润表型。我们的分析显示，与非浸润性肿瘤相比，浸润性肿瘤缺乏有利的PBRM1突变，并且富含不利的 9p21.3 染色体缺失，这证明了免疫表型与体细胞改变的潜在相互作用如何影响治疗效果。