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Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
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G3BP1 and SLU7 Jointly Promote Immune Evasion by Downregulating MHC-I via PI3K/Akt Activation in Bladder Cancer

Xianchong Zheng1,2, Jiawei Chen1,2,3, Minhua Deng1,2

  • 1Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|December 12, 2023
PubMed

Insights

Ras GTPase-activating protein-binding protein 1 (G3BP1) hinders immune checkpoint inhibitor (ICI) therapy effectiveness in advanced bladder cancer (BLCA). Targeting G3BP1 with EGCG may enhance anti-PD-1 treatment efficacy.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Immune checkpoint inhibitors (ICIs) are a promising second-line treatment for advanced bladder cancer (BLCA).
  • Tumor cells possess immune evasion mechanisms that limit ICI responsiveness.
  • Identifying factors contributing to ICI resistance is crucial for improving treatment outcomes.

Purpose of the Study:

  • To investigate the role of mRNA-binding proteins in mediating ICI resistance in advanced BLCA.
  • To identify novel therapeutic targets for overcoming immune evasion in BLCA.

Main Methods:

  • Cox regression analysis to screen for mRNA-binding proteins associated with ICI response.
  • In vitro and in vivo experiments to elucidate the mechanism of G3BP1 in immune evasion.
  • Assessment of epigallocatechin gallate (EGCG) efficacy in sensitizing BLCA cells to anti-PD-1 therapy in a mouse model.

Main Results:

  • Ras GTPase-activating protein-binding protein 1 (G3BP1) was identified as a key factor associated with diminished ICI effectiveness in BLCA.
  • G3BP1 promotes immune evasion by downregulating MHC-I expression via PI3K/Akt signaling activation.
  • G3BP1 interacts with SLU7 and other proteins to stabilize and enhance the translation of PI3K/Akt pathway components.
  • EGCG treatment impeded G3BP1-mediated immune evasion and sensitized BLCA cells to anti-PD-1 antibodies in mice.

Conclusions:

  • G3BP1 and SLU7 collaboratively drive immune evasion in advanced BLCA.
  • Targeting G3BP1 with EGCG represents a potential therapeutic strategy to enhance the efficacy of anti-PD-1 therapy in BLCA patients.
Keywords:
Ras GTPase-activating protein-binding protein 1bladder cancerepigallocatechin gallateimmune checkpoint inhibitorsimmune evasionmajor histocompatibility complex class I

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