Prostaglandin E2-EP2/EP4 signaling induces immunosuppression in human cancer by impairing bioenergetics and ribosome biogenesis in immune cells

While prostaglandin E 2 (PGE 2 ) 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...

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Published inNature communications Vol. 15; no. 1; pp. 9464 - 19
Main Authors Punyawatthananukool, Siwakorn, Matsuura, Ryuma, Wongchang, Thamrong, Katsurada, Nao, Tsuruyama, Tatsuaki, Tajima, Masaki, Enomoto, Yutaka, Kitamura, Toshio, Kawashima, Masahiro, Toi, Masakazu, Yamanoi, Koji, Hamanishi, Junzo, Hisamori, Shigeo, Obama, Kazutaka, Charoensawan, Varodom, Thumkeo, Dean, Narumiya, Shuh
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.11.2024
Nature Publishing Group
Nature Portfolio
Subjects
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49/31
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631/250/256/2515
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Antitumor activity
Bioenergetics
Biosynthesis
c-Myc protein
Cancer
CD8 antigen
Cell activation
Down-regulation
Gene expression
Gene sequencing
Glycolysis
Humanities and Social Sciences
Immune system
Immunosuppression
Innate immunity
Interleukin 2 receptors
Leukocyte migration
Lymphocytes
Lymphocytes T
Macrophages
multidisciplinary
Myc protein
Myeloid cells
Oxidative phosphorylation
Phosphorylation
Prostaglandin E2
Ribonucleic acid
Ribosomal proteins
RNA
Science
Science (multidisciplinary)
Stat5 protein
Tumor microenvironment
Tumor-infiltrating lymphocytes
Tumors
Yeast
Online AccessGet full text
ISSN2041-1723
2041-1723
DOI10.1038/s41467-024-53706-3

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Abstract While prostaglandin E 2 (PGE 2 ) 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 PGE 2 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 PGE 2 downregulates c-Myc and OXPHOS in M1-like macrophages. These results suggest that PGE 2 -EP4/EP2 signaling impairs both adaptive and innate immunity in TME by hampering bioenergetics and ribosome biogenesis of tumor-infiltrating immune cells. Mechanisms of prostaglandin E2 (PGE2)-mediated immunosuppression in the tumor microenvironment (TME) have been previously reported. Here, the authors profile PGE2 functions in human cancer, suggesting that prostaglandin E2-mediated signaling impairs the activity of human CD8+ T cells and macrophages by altering bioenergetics and ribosome biogenesis.
AbstractList While prostaglandin E 2 (PGE 2 ) 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 PGE 2 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 PGE 2 downregulates c-Myc and OXPHOS in M1-like macrophages. These results suggest that PGE 2 -EP4/EP2 signaling impairs both adaptive and innate immunity in TME by hampering bioenergetics and ribosome biogenesis of tumor-infiltrating immune cells. Mechanisms of prostaglandin E2 (PGE2)-mediated immunosuppression in the tumor microenvironment (TME) have been previously reported. Here, the authors profile PGE2 functions in human cancer, suggesting that prostaglandin E2-mediated signaling impairs the activity of human CD8+ T cells and macrophages by altering bioenergetics and ribosome biogenesis.
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.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.
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.Mechanisms of prostaglandin E2 (PGE2)-mediated immunosuppression in the tumor microenvironment (TME) have been previously reported. Here, the authors profile PGE2 functions in human cancer, suggesting that prostaglandin E2-mediated signaling impairs the activity of human CD8+ T cells and macrophages by altering bioenergetics and ribosome biogenesis.
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.
Author Tsuruyama, Tatsuaki
Kitamura, Toshio
Hamanishi, Junzo
Yamanoi, Koji
Charoensawan, Varodom
Toi, Masakazu
Narumiya, Shuh
Obama, Kazutaka
Punyawatthananukool, Siwakorn
Wongchang, Thamrong
Matsuura, Ryuma
Tajima, Masaki
Kawashima, Masahiro
Enomoto, Yutaka
Thumkeo, Dean
Katsurada, Nao
Hisamori, Shigeo
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  publication-title: J. Immunol.
  doi: 10.4049/jimmunol.148.9.2845
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  start-page: 1486
  year: 2023
  end-page: 1500
  ident: CR15
  article-title: Dual blockade of EP2 and EP4 signaling is required for optimal immune activation and antitumor activity against prostaglandin-expressing tumors
  publication-title: Cancer Res. Commun.
  doi: 10.1158/2767-9764.CRC-23-0249
– volume: 185
  year: 2023
  ident: CR24
  article-title: AN0025, a novel antagonist of PGE -receptor E-type 4 (EP4), in combination with total neoadjuvant treatment of advanced rectal cancer
  publication-title: Radiother. Oncol.
  doi: 10.1016/j.radonc.2023.109669
– volume: 40
  start-page: 7
  year: 2004
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  ident: CR35
  article-title: Generation of a conditional allele of the mouse prostaglandin EP4 receptor
  publication-title: Genesis
  doi: 10.1002/gene.20048
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Snippet While prostaglandin E 2 (PGE 2 ) is produced in human tumor microenvironment (TME), its role therein remains poorly understood. Here, we examine this issue by...
While prostaglandin E2 (PGE2) is produced in human tumor microenvironment (TME), its role therein remains poorly understood. Here, we examine this issue by...
Abstract While prostaglandin E2 (PGE2) is produced in human tumor microenvironment (TME), its role therein remains poorly understood. Here, we examine this...
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Antitumor activity
Bioenergetics
Biosynthesis
c-Myc protein
Cancer
CD8 antigen
Cell activation
Down-regulation
Gene expression
Gene sequencing
Glycolysis
Humanities and Social Sciences
Immune system
Immunosuppression
Innate immunity
Interleukin 2 receptors
Leukocyte migration
Lymphocytes
Lymphocytes T
Macrophages
multidisciplinary
Myc protein
Myeloid cells
Oxidative phosphorylation
Phosphorylation
Prostaglandin E2
Ribonucleic acid
Ribosomal proteins
RNA
Science
Science (multidisciplinary)
Stat5 protein
Tumor microenvironment
Tumor-infiltrating lymphocytes
Tumors
Yeast
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Title Prostaglandin E2-EP2/EP4 signaling induces immunosuppression in human cancer by impairing bioenergetics and ribosome biogenesis in immune cells
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Volume 15
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