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

Yongbo Yu1, Ye Liang2, Fei Xie2

  • 1Urology 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.

Cancer Letters
|May 18, 2024
PubMed

Insights

M2-TAMs secrete TGF-β, promoting bladder cancer immune evasion via PKM2 and PD-L1. Blocking TGF-β and PKM2 enhances anti-tumor immunity, offering a new therapeutic strategy for bladder cancer.

Area of Science:

  • Immunology
  • Oncology
  • Cancer Metabolism

Background:

  • Tumor-associated macrophages (TAMs) are key in the tumor microenvironment (TME), linked to poor prognosis and resistance to therapies like immunotherapy.
  • The precise mechanisms by which TAMs influence immune metabolism and immune checkpoint signaling within the TME are not fully understood.

Purpose of the Study:

  • To elucidate how M2-TAM-derived TGF-β impacts immune metabolism and PD-L1 expression in bladder cancer (BLCA).
  • To investigate the role of pyruvate kinase isoenzymes M2 (PKM2) in TGF-β-mediated immune evasion.
  • To evaluate therapeutic strategies targeting the TGF-β/PKM2/PD-L1 axis in BLCA.

Main Methods:

  • Analysis of TGF-β secretion by M2-TAMs and its effect on glycolysis in BLCA.
  • Investigating the mechanism of PKM2 regulation by TGF-β, including nuclear translocation of PKM2 dimer and p-STAT3.
  • Assessing the impact of SB-431542 (TGF-β blocker) and shikonin (PKM2 inhibitor) on PD-L1 expression, tumor growth, and anti-tumor immunity in BLCA models.

Main Results:

  • M2-TAM-derived TGF-β increases glycolysis in BLCA and promotes PD-L1-mediated immune evasion via PKM2.
  • TGF-β enhances PKM2 expression by promoting nuclear translocation of the PKM2 dimer-STAT3 complex, which drives PD-L1 expression.
  • SB-431542 and shikonin treatment significantly reduced PD-L1 levels, inhibited BLCA growth, and enhanced anti-tumor immune responses.

Conclusions:

  • M2-TAM-derived TGF-β drives PD-L1-mediated immune evasion in BLCA through PKM2 dimer-STAT3 nuclear translocation.
  • Combined blockade of TGF-β receptor and PKM2 inhibition presents a promising therapeutic approach for BLCA by combating tumor progression and immunosuppression.
Keywords:
Bladder cancerCombination immunotherapyPD-L1TGF-βTumor-associated macrophage

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