Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
Cancer Med. 2024 Apr;13(7):e7113. doi: 10.1002/cam4.7113.
In renal cell carcinoma (RCC), no clinically available biomarker has been utilized for checkpoint inhibitor immunotherapy (IO) + tyrosine kinase inhibitor (TKI) combinations. Galectin-1 overexpression is found in tumors, with potential immune-regulating roles.
RNA-sequencing was performed in two cohorts of RCC treated with IO/TKI combination therapy (ZS-MRCC, JAVELIN-101). Immunohistochemistry and flow cytometry were performed to investigate immune cell infiltration and function in the tumor microenvironment of RCC. The RECIST criteria were used to define response and progression-free survival (PFS).
Galectin-1 expression was elevated in RCC with higher stage (p < 0.001) and grade (p < 0.001). Galectin-1 expression was also elevated in non-responders of IO/TKI therapy (p = 0.047). High galectin-1 was related with shorter PFS in both ZS-MRCC cohort (p = 0.036) and JAVELIN-101 cohort (p = 0.005). Multivariate Cox analysis defined galectin-1 as an independent factor for PFS (HR 2.505; 95% CI 1.116-5.622; p = 0.026). In the tumor microenvironment, high galectin-1 was related with decreased GZMB+CD8+ T cells (Speraman's ρ = -0.31, p = 0.05), and increased PD1 + CD8+ T cells (Speraman's ρ = 0.40, p = 0.01). Besides, elevated number of regulatory T cells (p = 0.039) and fibroblasts (p = 0.011) was also found in high galectin-1 tumors. Finally, a random-forest score (RFscore) was built for predicting IO/TKI benefit. IO/TKI therapy showed benefit only in low-RFscore patients (HR 0.489, 95% CI 0.358-0.669, p < 0.001), rather than high-RFscore patients (HR 0.875, 95% CI 0.658-1.163, p = 0.357).
High galectin-1 indicated therapeutic resistance and shorter PFS of IO/TKI therapy. High galectin-1 also indicated CD8+ T cell dysfunction. High galectin-1 could be applied for patient selection of IO/TKI therapy in RCC.
在肾细胞癌（RCC）中，尚无临床可用的生物标志物用于检查点抑制剂免疫治疗（IO）+酪氨酸激酶抑制剂（TKI）联合治疗。半乳糖凝集素-1在肿瘤中过度表达，具有潜在的免疫调节作用。
对接受 IO/TKI 联合治疗的 RCC 患者的两个队列（ZS-MRCC、JAVELIN-101）进行 RNA 测序。进行免疫组织化学和流式细胞术检测以研究 RCC 肿瘤微环境中的免疫细胞浸润和功能。使用 RECIST 标准定义反应和无进展生存期（PFS）。
Galectin-1 在 RCC 中表达升高，且具有更高的分期（p<0.001）和分级（p<0.001）。Galectin-1 在 IO/TKI 治疗的无应答者中也升高（p=0.047）。Galectin-1 高表达与 ZS-MRCC 队列（p=0.036）和 JAVELIN-101 队列（p=0.005）的较短 PFS 相关。多变量 Cox 分析将 Galectin-1 定义为 PFS 的独立因素（HR 2.505；95%CI 1.116-5.622；p=0.026）。在肿瘤微环境中，Galectin-1 高表达与减少的 GZMB+CD8+T 细胞相关（Speraman's ρ=-0.31，p=0.05），并与增加的 PD1+CD8+T 细胞相关（Speraman's ρ=0.40，p=0.01）。此外，还发现 Galectin-1 高表达的肿瘤中调节性 T 细胞（p=0.039）和成纤维细胞（p=0.011）数量增加。最后，构建了一个随机森林评分（RFscore）来预测 IO/TKI 的获益。IO/TKI 治疗仅在低 RFscore 患者中获益（HR 0.489，95%CI 0.358-0.669，p<0.001），而不是高 RFscore 患者（HR 0.875，95%CI 0.658-1.163，p=0.357）。
Galectin-1 高表达提示 IO/TKI 治疗的耐药性和较短的 PFS。Galectin-1 还提示 CD8+T 细胞功能障碍。Galectin-1 可用于 RCC 患者的 IO/TKI 治疗选择。
