- Genitourinary cancer
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Favorable Immunotherapy Plus Tyrosine Kinase Inhibition Outcome of Renal Cell Carcinoma Patients with Low CDK5 Expression
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Xianglai Xu, Ying Wang, Zhaoyi Chen, Yanjun Zhu, Jiajun Wang, Jianming Guo
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Cancer Res Treat. 2023;55(4):1321-1336. Published online April 3, 2023
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DOI: https://doi.org/10.4143/crt.2022.1532
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 Abstract
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- Purpose
Immunotherapy (IO) plus tyrosine kinase inhibitor (TKI) has become the first-line treatment for advanced renal cell carcinoma, despite the lack of prognostic biomarkers. Cyclin-dependent kinase 5 (CDK5) affects the tumor microenvironment, which may influence the efficacy of TKI+IO.
Materials and Methods
Two cohorts from our center (Zhongshan Metastatic Renal Cell Carcinoma [ZS-MRCC] cohort, Zhongshan High-risk Localized Renal Cell Carcinoma [ZS-HRRCC] cohort) and one cohort from a clinical trial (JAVELIN-101) were enrolled. The expression of CDK5 of each sample was determined by RNA sequencing. Immune infiltration and T cell function were evaluated by flow cytometry and immunohistochemistry. Response and progression-free survival (PFS) were set as primary endpoints.
Results
Patients of low CDK5 expression showed higher objective response rate (60.0% vs. 23.3%) and longer PFS in both cohorts (ZS-MRCC cohort, p=0.014; JAVELIN-101 cohort, p=0.040). CDK5 expression was enhanced in non-responders (p < 0.05). In the ZS-HRRCC cohort, CDK5 was associated with decreased tumor-infiltrating CD8+ T cells, which was proved by immunohistochemistry (p < 0.05) and flow cytometry (Spearman’s ρ=–0.49, p < 0.001). In the high CDK5 subgroup, CD8+ T cells revealed a dysfunction phenotype with decreased granzyme B, and more regulatory T cells were identified. A predictive score was further constructed by random forest, involving CDK5 and T cell exhaustion features. The RFscore was also validated in both cohorts. By utilizing the model, more patients might be distinguished from the overall cohort. Additionally, only in the low RFscore did TKI+IO outperform TKI monotherapy.
Conclusion
High-CDK5 expression was associated with immunosuppression and TKI+IO resistance. RFscore based on CDK5 may be utilized as a biomarker to determine the optimal treatment strategy.
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Citations
Citations to this article as recorded by  - SPP1 expression indicates outcome of immunotherapy plus tyrosine kinase inhibition in advanced renal cell carcinoma
Xianglai Xu, Jinglai Lin, Jiahao Wang, Ying Wang, Yanjun Zhu, Jiajun Wang, Jianming Guo
Human Vaccines & Immunotherapeutics.2024;[Epub] CrossRef - Efficacy and Safety of Immuno-Oncology Plus Tyrosine Kinase Inhibitors as Late-Line Combination Therapy for Patients with Advanced Renal Cell Carcinoma
Shuzo Hamamoto, Yoshihiko Tasaki, Toshiharu Morikawa, Taku Naiki, Toshiki Etani, Kazumi Taguchi, Shoichiro Iwatsuki, Rei Unno, Tomoki Takeda, Takashi Nagai, Kengo Kawase, Yoshihisa Mimura, Yosuke Sugiyama, Atsushi Okada, Yoko Furukawa-Hibi, Takahiro Yasui
Journal of Clinical Medicine.2024; 13(12): 3365. CrossRef - PSMD2 overexpression as a biomarker for resistance and prognosis in renal cell carcinoma treated with immune checkpoint and tyrosine kinase inhibitors
Xianglai Xu, Jiahao Wang, Ying Wang, Yanjun Zhu, Jiajun Wang, Jianming Guo
Cellular Oncology.2024; 47(5): 1943. CrossRef - External validation of hemoglobin and neutrophil levels as predictors of the effectiveness of ipilimumab plus nivolumab for treating renal cell carcinoma
Shuzo Hamamoto, Yoshihiko Tasaki, Shimpei Yamashita, Junya Furukawa, Kazutoshi Fujita, Ryotaro Tomida, Makito Miyake, Noriyuki Ito, Hideto Iwamoto, Yosuke Sugiyama, Kazumi Taguchi, Takahiro Yasui
Frontiers in Oncology.2024;[Epub] CrossRef
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