Institute of Experimental Oncology, University Medical Center Bonn (UKB), Bonn, Germany.
Center for Integrated Oncology Aachen/Bonn/Cologne/Düsseldorf (CIO-ABCD), Bonn, Germany.
J Immunother Cancer. 2021 Aug;9(8). doi: 10.1136/jitc-2021-002949.
BACKGROUND: In metastatic clear cell renal cell carcinoma (ccRCC), different combination therapies, each including anti-PD-1 immune checkpoint blockade (ICB), are applied as first-line treatment. Robust predictive biomarkers for rational upfront therapy decisions are lacking, although they are urgently needed. Recently, we showed that promoter methylation predicts response to ICB in melanoma. Here, we aimed to investigate methylation in ccRCC and its utility to serve as a predictive biomarker for anti-PD-1 based ICB in metastatic ccRCC. METHODS: methylation was analyzed with regard to transcriptional gene activity (mRNA expression), intratumoral immune cell composition, and clinical course in two ccRCC cohorts obtained from The Cancer Genome Atlas (TCGA cohort, n=533) and the University Hospital Bonn (UHB Non-ICB Cohort, n=116). In addition, methylation as well as CD8 T cell infiltrates and PD-L1 expression were evaluated in pre-treatment samples from a multicenter cohort (RCC-ICB Cohort, n=71). Patients included in the RCC-ICB Cohort were treated with either first line anti-PD-1 based combination therapy (n=25) or monotherapy post-tyrosine kinase inhibition in second line or later. Analyses were performed with regard to treatment response according to RECIST, progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) following treatment initiation. RESULTS: promoter hypomethylation was significantly correlated with mRNA expression, lymphocyte infiltration, and poor OS in both primary ccRCC cohorts (TCGA: HR 0.30 (95% CI 0.18 to 0.49), p<0.001; UHB Non-ICB: HR 0.35 (95% CI 0.16 to 0.75), p=0.007). In contrast, promoter hypomethylation predicted response and, accordingly, favorable outcomes (PFS and OS) in patients with ICB-treated ccRCC, overcompensating the negative prognostic value of hypomethylation at initial diagnosis. Moreover, in multivariable Cox regression, promoter hypomethylation remained an independent predictor of improved outcome in ICB-treated ccRCC after co-adjustment of the International Metastatic Renal Cell Carcinoma Database Consortium score (HR 3.00 (95% CI 1.47 to 6.28), p=0.003). CONCLUSIONS: Our study suggests methylation as a powerful predictive biomarker for immunotherapy response in metastatic RCC.
背景：在转移性透明细胞肾细胞癌（ccRCC）中，不同的联合治疗方案，包括抗 PD-1 免疫检查点阻断（ICB），被用作一线治疗。尽管迫切需要，但目前仍缺乏合理的一线治疗决策的稳健预测性生物标志物。最近，我们表明 启动子甲基化可预测黑色素瘤对 ICB 的反应。在这里，我们旨在研究 ccRCC 中的 甲基化及其作为转移性 ccRCC 中基于抗 PD-1 的 ICB 的预测生物标志物的效用。
方法：我们分析了两个从癌症基因组图谱（TCGA 队列，n=533）和波恩大学医院（UHB 非 ICB 队列，n=116）获得的 ccRCC 队列中与转录基因活性（mRNA 表达）、肿瘤内免疫细胞组成和临床病程相关的 甲基化。此外，在多中心队列（RCC-ICB 队列，n=71）的预处理样本中评估了 甲基化以及 CD8 T 细胞浸润和 PD-L1 表达。RCC-ICB 队列中的患者接受了一线抗 PD-1 为基础的联合治疗（n=25）或酪氨酸激酶抑制二线或以后的单药治疗。根据 RECIST、无进展生存期（PFS）、无事件生存期（EFS）和治疗开始后的总生存期（OS）对治疗反应进行了分析。
结果：在两个原发性 ccRCC 队列中， 启动子低甲基化与 mRNA 表达、淋巴细胞浸润和较差的 OS 显著相关（TCGA：HR 0.30（95%CI 0.18 至 0.49），p<0.001；UHB 非 ICB：HR 0.35（95%CI 0.16 至 0.75），p=0.007）。相比之下， 启动子低甲基化预测了 ICB 治疗的 ccRCC 患者的反应，并相应地改善了预后（PFS 和 OS），从而弥补了初始诊断时 低甲基化的负预后价值。此外，在多变量 Cox 回归中，在调整国际转移性肾细胞癌数据库联盟评分后， 启动子低甲基化仍然是 ICB 治疗的 ccRCC 患者预后改善的独立预测因子（HR 3.00（95%CI 1.47 至 6.28），p=0.003）。
结论：我们的研究表明， 甲基化是转移性 RCC 免疫治疗反应的有力预测性生物标志物。
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