Thumkeo and Punyawatthananukool et al. demonstrated that PGE2-EP2/EP4 signaling promoted active inflammation through NF-κB-mediated upregulation of target proinflammatory and angiogenesis genes in myeloid cells and simultaneously induced immunosuppression through mregDC-mediated Ccl22 and Ccl17 production to facilitate Treg recruitment and activation in the tumor. EP2/EP4 inhibition reduced NF-κB dependent gene expression, decreased tumor-infiltrating Tregs, induced type I IFN gene signatures, and suppressed LLC1 tumor growth. Expression of PTGER2 and PTGER4 (encoding EP2 and EP4) together correlated with poor prognosis in several cancers.
Contributed by Shishir Pant
ABSTRACT: Active inflammation generally promotes immune activation. However, in the tumor microenvironment (TME), active inflammation occurs in parallel with immunosuppression, and both contribute to tumor growth. Why inflammation does not lead to immune activation in TME remains unclear. In this study, using the immune checkpoint inhibitor-insensitive mouse cancer model and single-cell RNA sequencing, we show that PGE2-EP2/EP4 signaling simultaneously promotes active inflammation by inducing expression of the NF-κB genes in myeloid cells and elicits immunosuppression by driving the mregDC (mature DC enriched in immunoregulatory molecules)-Treg (regulatory T cell) axis for Treg recruitment and activation in the tumor. Importantly, the EP2/EP4 expression level is strongly correlated with the gene signatures of both active inflammation and the mregDC-Treg axis and has significant prognosis value in various human cancers. Thus, PGE2-EP2/EP4 signaling functions as the key regulatory node linking active inflammation and immunosuppression in TME, which can be targeted by EP2 and EP4 antagonists for cancer therapeutics.
Author Info: (1) Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; Alliance Laboratory for Advanced Medical Research, Kyoto University
Author Info: (1) Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; Alliance Laboratory for Advanced Medical Research, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. Electronic address: d.thumkeo@mfour.med.kyoto-u.ac.jp. (2) Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. (3) Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. (4) Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. (5) Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. (6) Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. (7) Alliance Laboratory for Advanced Medical Research, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; Drug Discovery Research, Astellas Pharma, Tsukuba, Ibaraki 305-8585, Japan. (8) Drug Discovery Research, Astellas Pharma, Tsukuba, Ibaraki 305-8585, Japan. (9) Drug Discovery Research, Astellas Pharma, Tsukuba, Ibaraki 305-8585, Japan. (10) Drug Discovery Research, Astellas Pharma, Tsukuba, Ibaraki 305-8585, Japan. (11) Drug Discovery Research, Astellas Pharma, Tsukuba, Ibaraki 305-8585, Japan. (12) Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; System Biology of Diseases Research Unit, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; Integrative Computational BioScience (ICBS) Center, Mahidol University, Nakhon Pathom 73170, Thailand. (13) Department of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. (14) Department of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. (15) Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; Alliance Laboratory for Advanced Medical Research, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; AMED-FORCE, Japan Agency for Medical Research and Development, Chiyoda, Tokyo 100-0004, Japan. Electronic address: snaru@mfour.med.kyoto-u.ac.jp.
