Department of Urology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200032, China.
Department of Urology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, China.
Cell Oncol (Dordr). 2024 Oct;47(5):1943-1956. doi: 10.1007/s13402-024-00977-z. Epub 2024 Sep 2.
Integrated immune checkpoint inhibitors (ICIs) plus tyrosine kinase inhibitors (TKIs) are now the recommended first-line therapy to manage renal cell carcinoma (mRCC). Proteasome 26S subunit non-ATPase 2 (PSMD2) overexpression in tumors has been correlated with tumor progression. Currently, mRCC lacks an established biomarker for the combination of ICI+TKI.
This study involved RNA sequencing of RCC patients from two cohorts treated with ICI+TKI (ZS-MRCC and JAVELIN-Renal-101). We utilized immunohistochemistry alongside flow cytometry, aiming at assessing immune cell infiltration and functionality in high-risk localized RCC samples. Response and progression-free survival (PFS) were evaluated relying upon RECIST criteria.
PSMD2 was significantly overexpressed in advanced RCC and among non-responders to ICI+TKI therapy. Overexpressed PSMD2 was correlated with poor PFS in the ZS-MRCC and JAVELIN-101 cohorts. Multivariate Cox analysis validated PSMD2 as an independent PFS predictor. PSMD2 overexpression was related to a reduction in CD8 T cells, especially GZMB CD8 T cells, besides an increase in PD1 CD4 T cells. Additionally, tumors with high PSMD2 levels showed enhanced T cell exhaustion levels and a higher regulatory T cell presence. A Machine Learning (ML) model based on PSMD2 expression and other screened factors was subsequently developed to predict the effectiveness of ICI+TKI.
Elevated PSMD2 expression is linked to resistance and decreased PFS in mRCC patients undergoing ICI+TKI therapy. High PSMD2 levels are also associated with impaired function and increased exhaustion of tumor-infiltrating lymphocytes. An ML model incorporating PSMD2 expression could potentially identify patients who may have a higher likelihood of benefiting from ICI+TKI.
目前，针对肾细胞癌（mRCC），将免疫检查点抑制剂（ICIs）与酪氨酸激酶抑制剂（TKIs）联合应用已被推荐为一线治疗方案。肿瘤中 26S 蛋白酶体非 ATP 酶 2（PSMD2）的过度表达与肿瘤进展相关。目前，mRCC 缺乏针对 ICI+TKI 联合治疗的既定生物标志物。
本研究对接受 ICI+TKI（ZS-MRCC 和 JAVELIN-Renal-101）治疗的两个 RCC 患者队列进行了 RNA 测序。我们利用免疫组化和流式细胞术，旨在评估高危局限性 RCC 样本中的免疫细胞浸润和功能。根据 RECIST 标准评估反应和无进展生存期（PFS）。
PSMD2 在晚期 RCC 和对 ICI+TKI 治疗无反应的患者中显著过表达。在 ZS-MRCC 和 JAVELIN-101 队列中，过表达的 PSMD2 与较差的 PFS 相关。多变量 Cox 分析验证了 PSMD2 是 PFS 的独立预测因子。PSMD2 过表达与 CD8 T 细胞，特别是 GZMB CD8 T 细胞减少有关，同时 PD1 CD4 T 细胞增加。此外，高 PSMD2 水平的肿瘤显示出增强的 T 细胞耗竭水平和更高的调节性 T 细胞存在。随后基于 PSMD2 表达和其他筛选因素开发了一个机器学习（ML）模型，以预测 ICI+TKI 的疗效。
在接受 ICI+TKI 治疗的 mRCC 患者中，PSMD2 表达升高与耐药和 PFS 降低相关。高 PSMD2 水平还与肿瘤浸润淋巴细胞功能受损和耗竭增加相关。包含 PSMD2 表达的 ML 模型可能有助于识别可能从 ICI+TKI 治疗中获益更高的患者。
