Tumor-associated macrophage enhances PD-L1-mediated immune escape of bladder cancer through PKM2 dimer-STAT3 complex nuclear translocation

Yongbo Yu; Ye Liang; Fei Xie; Zhao Zhang; Pengfei Zhang; Xinzhao Zhao; Zhilei Zhang; Zhijuan Liang; Dan Li; Liping Wang; Yuanbin Chen; Lijiang Sun; Haitao Niu; Yonghua Wang

doi:10.1016/j.canlet.2024.216964

Tumor-associated macrophage enhances PD-L1-mediated immune escape of bladder cancer through PKM2 dimer-STAT3 complex nuclear translocation

Cancer Lett. 2024 May 16:593:216964. doi: 10.1016/j.canlet.2024.216964. Online ahead of print.

Authors

Yongbo Yu¹, Ye Liang², Fei Xie², Zhao Zhang³, Pengfei Zhang³, Xinzhao Zhao³, Zhilei Zhang⁴, Zhijuan Liang², Dan Li², Liping Wang², Yuanbin Chen², Lijiang Sun⁵, Haitao Niu⁶, Yonghua Wang⁷

Affiliations

¹ Urology Department, The Affiliated Hospital of Qingdao University, China; Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China; Medicine College, Qingdao University, Qingdao, China; Department of Urology, Weifang People's Hospital, Weifang Medical University, Weifang, China.
² Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
³ Urology Department, The Affiliated Hospital of Qingdao University, China; Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China; Medicine College, Qingdao University, Qingdao, China.
⁴ Department of Urology, Weifang People's Hospital, Weifang Medical University, Weifang, China.
⁵ Urology Department, The Affiliated Hospital of Qingdao University, China.
⁶ Urology Department, The Affiliated Hospital of Qingdao University, China; Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China. Electronic address: niuht0532@126.com.
⁷ Urology Department, The Affiliated Hospital of Qingdao University, China; Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China. Electronic address: wangyonghua@qdu.edu.cn.

PMID: 38762193
DOI: 10.1016/j.canlet.2024.216964

Abstract

Tumor-associated macrophages (TAMs) are important components of the tumor microenvironment (TME) and strongly associated with poor prognosis and drug resistance, including checkpoint blockade immunotherapy in solid tumor patients. However, the mechanism by which TAM affects immune metabolism reprogramming and immune checkpoint signalling pathway in the TME remains elusive. In this study we found that transforming growth factor-beta (TGF-β) secreted by M2-TAMs increased the level of glycolysis in bladder cancer (BLCA) and played important role in PD-L1-mediated immune evasion through pyruvate kinase isoenzymes M2 (PKM2). Mechanistically, TGF-β promoted high expression of PKM2 by promoting the nuclear translocation of PKM2 dimer in conjunction with phosphorylated signal transducer and activator of transcription (p-STAT3), which then exerted its kinase activity to promote PD-L1 expression in BLCA. Moreover, SB-431542 (TGF-β blocker) and shikonin (PKM2 inhibitor) significantly reduced PD-L1 expression and inhibited BLCA growth and organoids by enhancing anti-tumor immune responses. In conclusion, M2-TAM-derived TGF-β promotes PD-L1-mediated immune evasion in BLCA by increasing the PKM2 dimer-STAT3 complex nuclear translocation. Combined blockade of the TGF-β receptor and inhibition of PKM2 effectively prevent BLCA progression and immunosuppression, providing a potential targeted therapeutic strategy for BLCA.

Keywords: Bladder cancer; Combination immunotherapy; PD-L1; TGF-β; Tumor-associated macrophage.