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Tumor-Associated Glycan Exploits Adenosine Receptor 2A Signaling to Facilitate Immune Evasion

Jing-Yan Cheng1, Hsiu-Hui Tsai1, Jung-Tung Hung1

  • 1Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital Linkou Medical Center, 15, Wenhua 1st Rd., Taoyuan, 333, Taiwan.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|June 18, 2025
PubMed

Insights

Globo H ceramide (GHCer) activates adenosine signaling in tumors, suppressing T cell responses. This glycosphingolipid promotes regulatory T cells and enhances their immunosuppressive functions, highlighting a new cancer therapy target.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Biology

Background:

  • Adenosine signaling is a key immunosuppressive pathway in the tumor microenvironment.
  • Tumor-associated glycosphingolipids represent potential regulators of immune responses.
  • Targeting immunosuppressive mechanisms is a critical strategy in cancer therapy.

Purpose of the Study:

  • To investigate the role of Globo H ceramide (GHCer) in modulating the tumor microenvironment.
  • To elucidate the mechanisms by which GHCer influences T cell responses and immune suppression.
  • To identify GHCer as a potential therapeutic target for enhancing anti-tumor immunity.

Main Methods:

  • Investigated GHCer interaction with adenosine receptor 2A (A2AR).
  • Analyzed downstream cyclic AMP (cAMP) and protein kinase A (PKA) signaling pathways.
  • Assessed effects on CD4+ T cell proliferation and regulatory T cell (Treg) differentiation.
  • Quantified expression of inhibitory molecules (LAG3, CTLA-4, PD-L1) and IL-35 secretion.
  • Examined CD39 and CD73 expression on GHCer-induced Tregs.
  • Identified GHCer complex formation with TRAX and A2AR C-terminus.

Main Results:

  • GHCer activates A2AR signaling, leading to reduced CD4+ T cell proliferation.
  • GHCer promotes Treg differentiation and enhances their suppressive capacity.
  • Upregulation of inhibitory molecules (LAG3, CTLA-4, PD-L1) and IL-35 secretion by GHCer-induced Tregs.
  • GHCer-induced Tregs express CD39 and CD73, amplifying adenosine production and creating a positive feedback loop.
  • GHCer forms a complex with TRAX and A2AR, facilitating A2AR activation and promoting an immunosuppressive tumor microenvironment.

Conclusions:

  • GHCer plays a significant role in establishing an immunosuppressive tumor microenvironment through adenosine signaling.
  • GHCer-induced immune suppression involves dual effects on T cells: reduced proliferation and enhanced Treg function.
  • The interaction of GHCer with TRAX and A2AR provides a mechanistic basis for its immunosuppressive effects.
  • GHCer represents a promising therapeutic target for overcoming immune suppression in cancer.
Keywords:
Adenosine receptor 2AGlobo H ceramideTRAXTreg

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