Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
Scand J Immunol. 2023 Oct;98(4):e13304. doi: 10.1111/sji.13304. Epub 2023 Jun 16.
Checkpoint inhibitor immunotherapy plus tyrosine kinase inhibitor (IO/TKI) has become the first-line treatment for metastatic renal cell carcinoma (RCC), despite the lack of biomarkers. Cyclin-dependent kinase 6 (CDK6) has shown a regulatory role in antitumour response. The study enrolled two cohorts of metastatic RCC treated by IO/TKI (Zhongshan Hospital [ZS]-MRCC, n = 45; JAVELIN-101, n = 726) and two cohorts of localized RCC (ZS-HRRCC, n = 40; TCGA-KIRC, n = 530). CDK6 was evaluated by RNA-sequencing. Progression-free survival (PFS) was the primary endpoint. The prognostic role of CDK6 was evaluated by survival analysis. The correlation between CDK6 and tumour microenvironment was assessed by immunohistochemistry and flow cytometry. The high-CDK6 group displayed a lower response rate (13.6%) than the low-CDK6 group (56.5%) (P = .002). High-CDK6 was associated with poor PFS in both the ZS-MRCC cohort (high-CDK6, median PFS 6.4 months; low-CDK6, median PFS not reached; P = .010) and JAVELIN-101 cohort (high-CDK6, median PFS 10.0 months; low-CDK6, median PFS 13.3 month; P = .033). High-CDK6 was associated with increased PD1 CD8 T cells (Spearman's ρ = .47, P < .001) and decreased Granzyme B CD8 T cells (Spearman's ρ = -.35, P = .030). Finally, a random forest score (RFscore) was built by integrating CDK6 and immunologic genes, which was associated with survival benefits of IO/TKI (RFscore-low, TKI vs IO/TKI, HR = 2.47, 95% CI 1.82-3.35, P < .001; RFscore-high, TKI vs IO/TKI, HR = 0.99, 95% CI 0.75-1.32, P = .963). Elevated CDK6 expression indicated resistance and poor PFS under IO/TKI therapy, which was related to exhausted CD8 T cells. Integrated RFscore could evaluate the benefits of IO/TKI.
检查点抑制剂免疫治疗联合酪氨酸激酶抑制剂（IO/TKI）已成为转移性肾细胞癌（RCC）的一线治疗方法，尽管缺乏生物标志物。细胞周期蛋白依赖性激酶 6（CDK6）在抗肿瘤反应中表现出调节作用。该研究纳入了接受 IO/TKI 治疗的转移性 RCC 两个队列（中山医院 [ZS]-MRCC，n=45；JAVELIN-101，n=726）和局部 RCC 两个队列（ZS-HRRCC，n=40；TCGA-KIRC，n=530）。通过 RNA 测序评估 CDK6。无进展生存期（PFS）是主要终点。通过生存分析评估 CDK6 的预后作用。通过免疫组化和流式细胞术评估 CDK6 与肿瘤微环境的相关性。高 CDK6 组的缓解率（13.6%）低于低 CDK6 组（56.5%）（P=.002）。在 ZS-MRCC 队列（高 CDK6，中位 PFS 6.4 个月；低 CDK6，中位 PFS 未达到；P=.010）和 JAVELIN-101 队列（高 CDK6，中位 PFS 10.0 个月；低 CDK6，中位 PFS 13.3 个月；P=.033）中，高 CDK6 与较差的 PFS 相关。高 CDK6 与 PD1 CD8 T 细胞增加（Spearman's ρ=.47，P<.001）和 Granzyme B CD8 T 细胞减少相关（Spearman's ρ=-.35，P=.030）。最后，通过整合 CDK6 和免疫基因构建了一个随机森林评分（RFscore），该评分与 IO/TKI 的生存获益相关（RFscore-低，TKI 与 IO/TKI，HR=2.47，95%CI 1.82-3.35，P<.001；RFscore-高，TKI 与 IO/TKI，HR=0.99，95%CI 0.75-1.32，P=.963）。CDK6 表达升高表明 IO/TKI 治疗下的耐药性和较差的 PFS，这与耗竭的 CD8 T 细胞有关。整合的 RFscore 可以评估 IO/TKI 的获益。
