Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing100069, China.
Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing100069, China.
Int J Mol Sci. 2023 Apr 24;24(9):7755. doi: 10.3390/ijms24097755.
Clear cell renal cell carcinoma (ccRCC) is a highly immunogenic tumor and immune dysfunction is associated with ccRCC poor prognosis. The RhoGTPase-activating proteins (RhoGAPs) family was reported to affect ccRCC development, but its role in immunity and prognosis prediction for ccRCC remain unknown. In the current study, we found was the only independent risk factor among 33 RhoGAPs (hazard ratio [HR] 1.949, 95% confidence interval [CI] 1.364-2.785). High level was associated with shorter overall survival (OS, HR 2.040, 95% CI 1.646-3.417) and is a prognostic biomarker for ccRCC. knockdown suppressed renal cell carcinoma (RCC) cell proliferation, colony formation, and migration, suggesting the promoting role of on RCC development. Mechanistically, might contribute to the suppressive tumor immune microenvironment (TIME). High level was correlated with infiltration of immunosuppressive cells (including T helper 2 (Th2) cells, regulatory T (Treg) cells, myeloid derived suppressor cells (MDSC), and M2 macrophage cells), activation of immunosuppressive pathways (IL6-JAK-STAT3 signaling and IFNγ response), and expression of inhibitory immune checkpoints (ICs). could promote T cell exhaustion and induce immune escape. ccRCC patients with low level were more suitable for immune checkpoint inhibitors (ICIs) therapy, while those with high level might benefit from a combination of blockade and ICIs. In all, might serve as a novel prognostic marker, therapeutic target, and predictor in the clinical response to ICIs therapy for ccRCC.
透明细胞肾细胞癌 (ccRCC) 是一种高度免疫原性肿瘤，免疫功能障碍与 ccRCC 预后不良有关。RhoGTPase 激活蛋白 (RhoGAPs) 家族被报道影响 ccRCC 的发展，但它在 ccRCC 中的免疫作用和预后预测中的作用尚不清楚。在本研究中，我们发现 是 33 种 RhoGAPs 中唯一的独立危险因素 (风险比 [HR] 1.949，95%置信区间 [CI] 1.364-2.785)。高 水平与总生存期 (OS) 缩短相关 (HR 2.040，95%CI 1.646-3.417)，是 ccRCC 的预后生物标志物。 敲低抑制肾细胞癌 (RCC) 细胞增殖、集落形成和迁移，表明 对 RCC 发展具有促进作用。机制上， 可能有助于抑制肿瘤免疫微环境 (TIME)。高 水平与免疫抑制细胞浸润相关 (包括辅助性 T 细胞 2 (Th2) 细胞、调节性 T (Treg) 细胞、髓系来源的抑制细胞 (MDSC) 和 M2 巨噬细胞)、免疫抑制途径的激活 (IL6-JAK-STAT3 信号和 IFNγ 反应) 和抑制性免疫检查点 (ICs) 的表达相关。 可以促进 T 细胞耗竭并诱导免疫逃逸。ccRCC 患者中 水平较低更适合免疫检查点抑制剂 (ICIs) 治疗，而 水平较高的患者可能受益于 阻断联合 ICIs。总之， 可能成为 ccRCC 患者的一种新的预后标志物、治疗靶点和对 ICIs 治疗临床反应的预测因子。
