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Updated: May 29, 2026
The Use of Reverse Phase Protein Arrays RPPA to Explore Protein Expression Variation within Individual Renal Cell Cancers
Published on: January 22, 2013
KPNA2 expression as a biomarker for immunosuppressive microenvironment predicting response to TKI and immunotherapy
Xianglai Xu1, Xin Xie2, Jiajun Wang3
1Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Urology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China.
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.
Insights
Karyopherin alpha2 subunit (KPNA2) predicts response to advanced renal cell carcinoma (RCC) treatment. Low KPNA2 expression indicates better outcomes with immunotherapy plus tyrosine kinase inhibitors, while high KPNA2 suggests resistance.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Advanced renal cell carcinoma (RCC) treatment combines immunotherapy (IO) and tyrosine kinase inhibitors (TKI).
- Predictive biomarkers for TKI+IO therapy in advanced RCC are lacking.
- Karyopherin alpha2 subunit (KPNA2) is implicated in cancer progression and therapy resistance.
Purpose of the Study:
- To investigate KPNA2 as a predictive biomarker for TKI+IO therapy in advanced RCC.
- To evaluate the association between KPNA2 expression and treatment response, progression-free survival (PFS), and immune microenvironment.
Main Methods:
- Analysis of two patient cohorts (ZS-MRCC and JAVELIN Renal 101 trial).
- Quantification of KPNA2 expression via RNA sequencing.
- Assessment of immune cell infiltration and T-cell functionality using flow cytometry and multiplex immunohistochemistry (IHC).
Main Results:
- Low KPNA2 expression correlated with superior objective response rates (55% vs. 20%) and prolonged PFS.
- High KPNA2 tumors showed increased tumor-infiltrating lymphocytes (TILs) but impaired CD8+ T-cell function (reduced granzyme B).
- Elevated KPNA2 was associated with increased regulatory T cells (Tregs) and decreased M1-like macrophages.
Conclusions:
- KPNA2 expression mediates immunosuppression and resistance to TKI+IO therapy in advanced RCC.
- KPNA2 serves as a potential biomarker for personalizing treatment strategies in advanced RCC.
- Findings may guide optimization of TKI+IO versus alternative regimens based on KPNA2 levels.
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