综合免疫检查点抑制剂（ICIs）加酪氨酸激酶抑制剂（TKI）现在是治疗肾细胞癌（mRCC）的推荐一线疗法。肿瘤中蛋白酶体 26S 亚基非 ATP 酶 2 (PSMD2) 过度表达与肿瘤进展相关。目前，mRCC 缺乏 ICI TKI 组合的既定生物标志物。本研究涉及对接受 ICI TKI 治疗的两组 RCC 患者（ZS-MRCC 和 JAVELIN-Renal-101）进行 RNA 测序。我们利用免疫组织化学和流式细胞术，旨在评估高风险局部肾细胞癌样本中的免疫细胞浸润和功能。根据 RECIST 标准评估缓解和无进展生存 (PFS)。PSMD2 在晚期 RCC 和 ICI TKI 治疗无反应者中显着过度表达。在 ZS-MRCC 和 JAVELIN-101 队列中，过度表达的 PSMD2 与不良 PFS 相关。多变量 Cox 分析验证 PSMD2 作为独立的 PFS 预测因子。 PSMD2 过表达除了 PD1 CD4 T 细胞增加外，还与 CD8 T 细胞（尤其是 GZMB CD8 T 细胞）减少有关。此外，PSMD2 水平高的肿瘤表现出 T 细胞耗竭水平增强和调节性 T 细胞含量更高。随后开发了基于 PSMD2 表达和其他筛选因素的机器学习 (ML) 模型来预测 ICI TKI 的有效性。 PSMD2 表达升高与接受 ICI TKI 治疗的 mRCC 患者的耐药性和 PFS 降低有关。高 PSMD2 水平还与功能受损和肿瘤浸润淋巴细胞耗竭增加有关。结合 PSMD2 表达的 ML 模型可能会识别出更有可能从 ICI TKI 中受益的患者。© 2024。Springer Nature Switzerland AG。

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.© 2024. Springer Nature Switzerland AG.