Purpose: PD-L1 expression on tumor cells (TC) is associated with response to anti-PD-1-based therapies in some tumor types, but its significance in clear cell renal cell carcinoma (ccRCC) is uncertain. We leveraged tumor heterogeneity to identify molecular correlates of TC PD-L1 expression in ccRCC and assessed their role in predicting response to anti-PD-1 monotherapy. Experimental Design: RNA sequencing was performed on paired TC PD-L1 positive and negative areas isolated from eight ccRCC tumors and transcriptomic features associated with PD-L1 status were identified. A cohort of 232 patients with metastatic ccRCC from the randomized CheckMate-025 (CM-025) trial was used to confirm the findings and correlate transcriptomic profiles with clinical outcomes. Results: In both the paired samples and the CM-025 cohort, TC PD-L1 expression was associated with combined overexpression of immune- and cell proliferation–related pathways, upregulation of T-cell activation signatures, and increased tumor-infiltrating immune cells. In the CM-025 cohort, TC PD-L1 expression was not associated with clinical outcomes. A molecular RCC subtype characterized by combined overexpression of immune- and cell proliferation–related pathways (previously defined by unsupervised clustering of transcriptomic data) was enriched in TC PD-L1 positive tumors and displayed longer progression-free survival (HR, 0.32; 95% confidence interval, 0.13–0.83) and higher objective response rate (30% vs. 0%, P = 0.04) on nivolumab compared with everolimus. Conclusions: Both TC-extrinsic (immune-related) and TC-intrinsic (cell proliferation–related) mechanisms are likely intertwined in the regulation of TC PD-L1 expression in ccRCC. The quantitation of these transcriptional programs may better predict benefit from anti-PD-1-based therapy compared with TC PD-L1 expression alone in ccRCC.

中文翻译：

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转移性透明细胞肾细胞癌肿瘤细胞 PD-L1 表达与纳武单抗单药治疗反应的转录组相关性

目的：肿瘤细胞 (TC) 上的 PD-L1 表达与某些肿瘤类型对基于抗 PD-1 的治疗的反应相关，但其在透明细胞肾细胞癌 (ccRCC) 中的意义尚不确定。我们利用肿瘤异质性来识别 ccRCC 中 TC PD-L1 表达的分子相关性，并评估它们在预测抗 PD-1 单一疗法反应中的作用。实验设计：对从 8 个 ccRCC 肿瘤中分离出的配对 TC PD-L1 阳性和阴性区域进行 RNA 测序，并鉴定了与 PD-L1 状态相关的转录组特征。来自随机 CheckMate-025 (CM-025) 试验的 232 名转移性 ccRCC 患者队列被用来证实研究结果并将转录组谱与临床结果相关联。结果：在配对样本和 CM-025 队列中，TC PD-L1 表达与免疫和细胞增殖相关途径的联合过度表达、T 细胞激活特征的上调以及肿瘤浸润免疫细胞的增加有关。在 CM-025 队列中，TC PD-L1 表达与临床结果无关。以免疫和细胞增殖相关途径（之前由转录组数据的无监督聚类定义）联合过表达为特征的分子 RCC 亚型在 TC PD-L1 阳性肿瘤中富集，并表现出更长的无进展生存期（HR，0.32；95%）与依维莫司相比，纳武单抗的置信区间（0.13-0.83）和更高的客观缓解率（30% vs. 0%，P = 0.04）。结论：TC 外在（免疫相关）和 TC 内在（细胞增殖相关）机制可能在 ccRCC 中 TC PD-L1 表达的调节中交织在一起。与 ccRCC 中单独的 TC PD-L1 表达相比，这些转录程序的定量可以更好地预测基于抗 PD-1 的治疗的益处。