Tumor‐Associated Glycan Exploits Adenosine Receptor 2A Signaling to Facilitate Immune Evasion
Jing‐Yan Cheng, Hsiu‐Hui Tsai, Jung‐Tung Hung, Tsai‐Hsien Hung, Chun‐Cheng Lin, Chien‐Wei Lee, Zi‐Chi Lo, Jingrong Huang, Shih‐Pin Chiou, Yenlin Huang, Shih‐Hsiang Chen, Chun‐Nan Yeh, John Yu, Alice L. Yu
Abstract
Abstract Adenosine signaling is a crucial immunosuppressive pathway within the tumor microenvironment, making it a promising target for cancer therapy. In this study, it is demonstrated that Globo H ceramide (GHCer), the most prevalent tumor‐associated glycosphingolipid, influences the tumor microenvironment by activating adenosine signaling, which results in dual immunosuppressive effects on T cells. It is demonstrated that GHCer interacts with the adenosine receptor 2A (A2AR), triggering cyclic AMP (cAMP) and protein kinase A (PKA) signaling. This interaction leads to a reduction in the proliferation of CD4 + T cells while simultaneously promoting the differentiation of regulatory T cells (Tregs). Furthermore, GHCer enhances the suppressive capacity of Treg cells by upregulating inhibitory molecules such as Lymphocyte‐activation gene 3 (LAG3), cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4), Programmed cell death 1 ligand 1 (PD‐L1), and it stimulates the secretion of the immunosuppressive cytokine Interleukin 35 (IL‐35). Additionally, GHCer‐induced Tregs express CD39 and CD73, which further enhances adenosine production and creates a positive feedback loop in the adenosinergic pathway and A2AR signaling. Mechanistically, it is found that GHCer forms a complex with TRAX (translin‐associated factor‐X) and the C‐terminus of A2AR, which facilitates the activation of A2AR and promotes an immunosuppressive tumor microenvironment.