Prostaglandin E<inf>2</inf>-EP2/EP4 signaling induces immunosuppression in human cancer by impairing bioenergetics and ribosome biogenesis in immune cells
Issued Date
2024-11-01
Resource Type
eISSN
20411723
Scopus ID
2-s2.0-85208291632
Pubmed ID
39487111
Journal Title
Nature communications
Volume
15
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Nature communications Vol.15 No.1 (2024) , 9464
Suggested Citation
Punyawatthananukool S., Matsuura R., Wongchang T., Katsurada N., Tsuruyama T., Tajima M., Enomoto Y., Kitamura T., Kawashima M., Toi M., Yamanoi K., Hamanishi J., Hisamori S., Obama K., Charoensawan V., Thumkeo D., Narumiya S. Prostaglandin E<inf>2</inf>-EP2/EP4 signaling induces immunosuppression in human cancer by impairing bioenergetics and ribosome biogenesis in immune cells. Nature communications Vol.15 No.1 (2024) , 9464. doi:10.1038/s41467-024-53706-3 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/101996
Title
Prostaglandin E<inf>2</inf>-EP2/EP4 signaling induces immunosuppression in human cancer by impairing bioenergetics and ribosome biogenesis in immune cells
Author's Affiliation
Institute of Biomedical Research and Innovation
Foundation for Biomedical Research and Innovation at Kobe
Faculty of Science, Mahidol University
Siriraj Hospital
Japan Agency for Medical Research and Development
Graduate School of Medicine
University of Phayao
Suranaree University of Technology
The University of Tokyo
Kyoto Tachibana University
Mahidol University
Foundation for Biomedical Research and Innovation at Kobe
Faculty of Science, Mahidol University
Siriraj Hospital
Japan Agency for Medical Research and Development
Graduate School of Medicine
University of Phayao
Suranaree University of Technology
The University of Tokyo
Kyoto Tachibana University
Mahidol University
Corresponding Author(s)
Other Contributor(s)
Abstract
While prostaglandin E2 (PGE2) is produced in human tumor microenvironment (TME), its role therein remains poorly understood. Here, we examine this issue by comparative single-cell RNA sequencing of immune cells infiltrating human cancers and syngeneic tumors in female mice. PGE receptors EP4 and EP2 are expressed in lymphocytes and myeloid cells, and their expression is associated with the downregulation of oxidative phosphorylation (OXPHOS) and MYC targets, glycolysis and ribosomal proteins (RPs). Mechanistically, CD8+ T cells express EP4 and EP2 upon TCR activation, and PGE2 blocks IL-2-STAT5 signaling by downregulating Il2ra, which downregulates c-Myc and PGC-1 to decrease OXPHOS, glycolysis, and RPs, impairing migration, expansion, survival, and antitumor activity. Similarly, EP4 and EP2 are induced upon macrophage activation, and PGE2 downregulates c-Myc and OXPHOS in M1-like macrophages. These results suggest that PGE2-EP4/EP2 signaling impairs both adaptive and innate immunity in TME by hampering bioenergetics and ribosome biogenesis of tumor-infiltrating immune cells.