BAP1 相关特征可预测 ccRCC 患者接受免疫治疗对比 VEGFR/mTOR 抑制剂的获益：JAVELIN Renal 101 与 checkmate-009/010/025 试验的回顾性分析。
BAP1-related signature predicts benefits from immunotherapy over VEGFR/mTOR inhibitors in ccRCC: a retrospective analysis of JAVELIN Renal 101 and checkmate-009/010/025 trials.
机构信息
Department of Urology, The Third Medical Center of PLA General Hospital, Yongding Road 69, Haidian District, Beijing, 100039, China.
Burning Rock Biotech, Guangzhou, Guangdong, China.
出版信息
Cancer Immunol Immunother. 2023 Aug;72(8):2557-2572. doi: 10.1007/s00262-023-03424-4. Epub 2023 Apr 12.
BACKGROUND
In patients with advanced clear cell renal cell carcinoma, despite the undoubted benefits from immune checkpoint inhibitor (ICI)-based therapies over monotherapies of angiogenic/mTOR inhibitors in the intention-to-treat population, approximately a quarter of the patients can scarcely gain advantage from ICIs, prompting the search for predictive biomarkers for patient selection.
METHODS
Clinical and multi-omic data of 2428 ccRCC patients were obtained from The Cancer Genome Atlas (TCGA, n = 537), JAVELIN Renal 101 (avelumab plus axitinib vs. sunitinib, n = 885), and CheckMate-009/010/025 (nivolumab vs. everolimus, n = 1006).
RESULTS
BAP1 mutations were associated with large progression-free survival (PFS) benefits from ICI-based immunotherapies over sunitinib/everolimus (pooled estimate of interaction HR = 0.71, 95% CI 0.51-0.99, P = 0.045). Using the top 20 BAP1 mutation-associated differentially expressed genes (DEGs) generated from the TCGA cohort, we developed the BAP1-score, negatively correlated with angiogenesis and positively correlated with multiple immune-related signatures concerning immune cell infiltration, antigen presentation, B/T cell receptor, interleukin, programmed death-1, and interferon. A high BAP1-score indicated remarkable PFS benefits from ICI-based immunotherapies over angiogenic/mTOR inhibitors (avelumab plus axitinib vs. sunitinib: HR = 0.55, 95% CI 0.43-0.70, P < 0.001; nivolumab vs. everolimus: HR = 0.72, 95% CI 0.52-1.00, P = 0.045), while these benefits were negligible in the low BAP1-score subgroup (HR = 1.16 and 1.02, respectively).
CONCLUSION
In advanced ccRCCs, the BAP1-score is a biologically and clinically significant predictor of immune microenvironment and the clinical benefits from ICI-based immunotherapies over angiogenic/mTOR inhibitors, demonstrating its potential utility in optimizing the personalized therapeutic strategies in patients with advanced ccRCC.
背景
在晚期透明细胞肾细胞癌患者中，尽管免疫检查点抑制剂（ICI）治疗在治疗意向人群中明显优于血管生成/mTOR 抑制剂的单药治疗，但仍有约四分之一的患者几乎无法从 ICI 中获益，因此需要寻找预测生物标志物来进行患者选择。
方法
从癌症基因组图谱（TCGA，n=537）、JAVELIN Renal 101（avelumab 加 axitinib 与 sunitinib，n=885）和 CheckMate-009/010/025（nivolumab 与 everolimus，n=1006）获得了 2428 例 ccRCC 患者的临床和多组学数据。
结果
BAP1 突变与 ICI 为基础的免疫治疗与 sunitinib/everolimus 相比具有较大的无进展生存期（PFS）获益（交互 HR=0.71，95%CI 0.51-0.99，P=0.045）。利用 TCGA 队列生成的 top 20 个 BAP1 突变相关差异表达基因（DEGs），我们开发了 BAP1 评分，该评分与血管生成呈负相关，与多个免疫相关特征呈正相关，包括免疫细胞浸润、抗原呈递、B/T 细胞受体、白细胞介素、程序性死亡受体-1 和干扰素。高 BAP1 评分与 ICI 为基础的免疫治疗与血管生成/mTOR 抑制剂相比具有显著的 PFS 获益（avelumab 加 axitinib 与 sunitinib：HR=0.55，95%CI 0.43-0.70，P<0.001；nivolumab 与 everolimus：HR=0.72，95%CI 0.52-1.00，P=0.045），而在低 BAP1 评分亚组中获益微不足道（HR=1.16 和 1.02）。
结论
在晚期 ccRCC 中，BAP1 评分是免疫微环境的生物学和临床意义上的预测因子，也是 ICI 为基础的免疫治疗与血管生成/mTOR 抑制剂相比的临床获益的预测因子，表明其在优化晚期 ccRCC 患者的个体化治疗策略方面具有潜在的应用价值。
Zotero 插件