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; Jing-Rong Huang; Shih-Pin Chiou; Yenlin Huang; Shih-Hsiang Chen; Chun-Nan Yeh; John Yu; Alice L Yu

doi:10.1002/advs.202416501

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

Adv Sci (Weinh). 2025 Jun 18:e2416501. doi: 10.1002/advs.202416501. Online ahead of print.

Authors

Jing-Yan Cheng¹, Hsiu-Hui Tsai¹, Jung-Tung Hung¹, Tsai-Hsien Hung¹, Chun-Cheng Lin², Chien-Wei Lee¹, Zi-Chi Lo¹, Jing-Rong Huang¹, Shih-Pin Chiou¹, Yenlin Huang^{1

3

4}, Shih-Hsiang Chen^{5

6}, Chun-Nan Yeh^{1

4

7

8}, John Yu^{1

6

9}, Alice L Yu^{1

6

10

11}

Affiliations

¹ Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital Linkou Medical Center, 15, Wenhua 1st Rd., Taoyuan, 333, Taiwan.
² Department of Chemistry, National Tsing Hua University, 101, Sec. 2, Kuang-Fu Rd., Hsinchu, 300, Taiwan.
³ Department of Anatomic Pathology, Chang Gung Memorial Hospital at Linko, 5, Fuxing St., Taoyuan, 333, Taiwan.
⁴ School of Medicine, National Tsing Hua University, 101, Sec. 2, Kuang-Fu Rd., Hsinchu, 300, Taiwan.
⁵ Department of Pediatrics, Division of Hematology-Oncology, Chang Gung Memorial Hospital, 5, Fuxing St., Taoyuan, 333, Taiwan.
⁶ College of Medicine, Chang Gung University, 259, Wenhua 1st Rd., Taoyuan, 333, Taiwan.
⁷ Chang Gung University, 259, Wenhua 1st Rd., Taoyuan, 333, Taiwan.
⁸ Department of Surgery and Liver Research Center, Chang Gung Memorial Hospital, 5, Fuxing St., Taoyuan, 333, Taiwan.
⁹ Institute of Cellular and Organismic Biology, Academia Sinica, 128, Section 2, Academia Rd., Taipei, 115, Taiwan.
¹⁰ Genomics Research Center, Academia Sinica, 128 Section 2, Academia Rd., Taipei, 115, Taiwan.
¹¹ Department of Pediatrics, University of California San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA.

PMID: 40532063
DOI: 10.1002/advs.202416501

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.

Keywords: Adenosine receptor 2A; Globo H ceramide; TRAX; Treg.

Abstract

Grants and funding