KPNA2 expression as a biomarker for immunosuppressive microenvironment predicting response to TKI and immunotherapy in metastatic renal cell carcinoma

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology Pub Date : 2025-09-03 DOI:10.1016/j.ejphar.2025.178120

Xianglai Xu , Xin Xie , Jiajun Wang , Tianxiang Chen , Yanjun Zhu

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引用次数: 0

Abstract

Background

Immunotherapy (IO) combined with tyrosine kinase inhibitors (TKI) are now first-line therapy for advanced renal cell carcinoma (RCC), though reliable predictive biomarkers remain elusive. Recent evidence demonstrates that karyopherin α2 subunit (KPNA2), a nuclear transport regulator, plays key roles in tumorigenesis and therapy resistance.

Methods

Two cohorts were analyzed: an institutional cohort of metastatic RCC patients (ZS-MRCC) and the phase III JAVELIN Renal 101 trial cohort. RNA sequencing quantified KPNA2 expression in all samples. Immune infiltration and T-cell functionality were evaluated using flow cytometry and multiplex immunohistochemistry (IHC).

Results

Patients with low KPNA2 expression demonstrated superior objective response rates (55 % vs. 20 %) and prolonged progression-free survival (PFS) in both cohorts. Responders showed significantly decreased KPNA2 expression (P < 0.05). Although, high-KPNA2 tumors exhibited increased tumor-infiltrating lymphocytes (TILs) by IHC (P < 0.05) and flow cytometry (P < 0.05), CD8⁺ T cells displayed functional impairment with reduced granzyme B (GZMB) expression. Elevated KPNA2 correlated positively with regulatory T cells (Tregs) and negatively with M1-like macrophages. A machine learning model incorporating KPNA2 and T-cell exhaustion markers generated a predictive score.

Conclusions

KPNA2 expression mediates immunosuppression and resistance to TKI + IO therapy. These findings position KPNA2 as a promising biomarker for personalizing treatment selection in advanced RCC, particularly for optimizing TKI + IO versus alternative regimens.

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KPNA2表达作为预测转移性肾细胞癌对TKI和免疫治疗反应的免疫抑制微环境的生物标志物

背景：免疫疗法（IO）联合酪氨酸激酶抑制剂（TKI）目前是晚期肾细胞癌（RCC）的一线治疗方法，尽管可靠的预测性生物标志物仍然难以捉摸。最近的研究表明，核丝蛋白α2亚基（KPNA2）是一种核转运调节因子，在肿瘤发生和治疗耐药中起关键作用。方法：对两个队列进行分析：转移性肾癌患者（ZS-MRCC）的机构队列和JAVELIN肾101 III期试验队列。RNA测序量化了所有样本中KPNA2的表达。采用流式细胞术和多重免疫组织化学（IHC）评价免疫浸润和t细胞功能。结果：在两个队列中，低KPNA2表达的患者表现出更高的客观缓解率（55%对20%）和更长的无进展生存期（PFS）。应答者的KPNA2表达明显降低（P < 0.05）。虽然高kpna2肿瘤通过免疫组化（IHC）和流式细胞术（P < 0.05）显示肿瘤浸润淋巴细胞（til）增加（P < 0.05），但CD8+ T细胞表现出功能障碍，颗粒酶B （GZMB）表达降低。升高的KPNA2与调节性T细胞（Tregs）呈正相关，与m1样巨噬细胞负相关。结合KPNA2和t细胞耗竭标志物的机器学习模型产生了预测性评分。结论：KPNA2表达介导TKI+IO治疗的免疫抑制和耐药。这些发现将KPNA2定位为晚期RCC个性化治疗选择的有希望的生物标志物，特别是在优化TKI+IO与替代方案方面。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European journal of pharmacology 医学-药学

CiteScore

9.00

自引率

0.00%

发文量

572

审稿时长

34 days

期刊介绍： The European Journal of Pharmacology publishes research papers covering all aspects of experimental pharmacology with focus on the mechanism of action of structurally identified compounds affecting biological systems. The scope includes: Behavioural pharmacology Neuropharmacology and analgesia Cardiovascular pharmacology Pulmonary, gastrointestinal and urogenital pharmacology Endocrine pharmacology Immunopharmacology and inflammation Molecular and cellular pharmacology Regenerative pharmacology Biologicals and biotherapeutics Translational pharmacology Nutriceutical pharmacology.