Galectin-1 对肾细胞癌免疫检查点联合酪氨酸激酶抑制的预后和反应性的影响。
Effect of galectin-1 on prognosis and responsiveness of immune checkpoint plus tyrosine kinase inhibition in renal cell carcinoma.
机构信息
Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
出版信息
Cancer Med. 2024 Apr;13(7):e7113. doi: 10.1002/cam4.7113.
BACKGROUND
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.
METHODS
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).
RESULTS
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).
CONCLUSIONS
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.
背景
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。
方法
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）。
结果
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）。
结论
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。
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