PGE₂-EP2/EP4 signaling elicits immunosuppression by driving the mregDC-Treg axis in inflammatory tumor microenvironment

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  • タムケオ, ディーン
    Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine; Alliance Laboratory for Advanced Medical Research, Kyoto University Graduate School of Medicine
  • パンヤワタナヌクーン, シワコン
    Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine
  • Prasongtanakij, Somsak
    Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine; Present address: Office of Research, Academic Affairs and Innovation, Faculty of Medicine Ramathibodi Hospital, Mahidol University
  • 松浦, 竜真
    Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine
  • 有馬, 健太郎
    Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine
  • Nie, Huan
    Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine
  • 山本, 梨絵
    Alliance Laboratory for Advanced Medical Research, Kyoto University Graduate School of Medicine; Drug Discovery Research, Astellas Pharma
  • 青山, 尚寛
    Drug Discovery Research, Astellas Pharma
  • 濱口, 壽雄
    Drug Discovery Research, Astellas Pharma
  • Sugahara, Shingo
    Drug Discovery Research, Astellas Pharma
  • 武田, 忍
    Drug Discovery Research, Astellas Pharma
  • チャルンサワン, ワロドム
    Department of Biochemistry, Faculty of Science, Mahidol University; System Biology of Diseases Research Unit, Faculty of Science, Mahidol University; Integrative Computational BioScience (ICBS) Center, Mahidol University
  • 田中, 淳
    Department of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University
  • 坂口, 志文
    Department of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University
  • 成宮, 周
    Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine; Alliance Laboratory for Advanced Medical Research, Kyoto University Graduate School of Medicine; AMED-FORCE, Japan Agency for Medical Research and Development

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説明

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.

収録刊行物

  • Cell Reports

    Cell Reports 39 (10), 110914-, 2022-06

    Elsevier BV

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