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EP4

EP4 pathway expressed on a myeloid-derived suppressor cell and tumor cell diagram

Prostaglandin E receptor 4 (EP4) can suppress innate and adaptive immune responses and promote tumor progression. Inhibition of EP4 can decrease immunosuppressive immune cells and promote innate and adaptive immune responses.

  • EP4 is a prostanoid receptor expressed by myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), dendritic cells (DCs), CD8+ effector T cells, natural killer (NK) cells, and other immune cells1-6
  • EP4 is a G-protein coupled receptor that suppresses both innate and adaptive immune functions3,4,7
    • When EP4 engages its ligand, prostaglandin E2 (PGE2), subsequent signal transduction leads to increased infiltration of immunosuppressive cells (eg, MDSCs and TAMs) and suppression of immune effector cells (eg, CD8+ T cells and NK cells)7
    • PGE2-EP4 interactions have been implicated in promoting regulatory T cell (Treg) development7
  • Preclinical evidence suggests that blocking PGE2 signaling through EP4 receptors leads to decreased MDSCs/TAMs numbers and increased cytotoxic T- and NK-cell activity1-4
  • Research suggests that dual blockade of EP4 and other checkpoint pathways can enhance T-cell activity within the tumor microenvironment10

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REFERENCES–EP4

1. Hata AN, Breyer RM. Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol Ther. 2004;103(2):147-166. 2. Majumder M, Xin X, Liu L, Girish GV, Lala PK. Prostaglandin E2 receptor EP4 as the common target on cancer cells and macrophages to abolish angiogenesis, lymphangiogenesis, metastasis, and stem-like cell functions. Cancer Sci. 2014;105(9):1142-1151. 3. Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res. 2007;67(9):4507-4513. 4. Holt D, Ma X, Kundu N, Fulton A. Prostaglandin E2 (PGE2) suppresses natural killer cell function primarily through the PGE2 receptor EP4. Cancer Immunol Immunother. 2011;60(11):1577-1586. 5. Chou JP, Ramirez CM, Ryba DM, Koduri MP, Effros RB. Prostaglandin E2 promotes features of replicative senescence in chronically activated human CD8+ T cells. PLoS One. 2014;9(6):e99432. 6. Legler DF, Krause P, Scandella E, Singer E, Groettrup M. Prostaglandin E2 is generally required for human dendritic cell migration and exerts its effect via EP2 and EP4 receptors. The Journal of Immunology. 2006;176(2):966-73. 7. Kalinski P. Regulation of immune responses by prostaglandin E2. J Immunol. 2012;188(1):21-28. 8. Rong Y, Yuan CH, Qu Z, et al. Doxorubicin resistant cancer cells activate myeloid-derived suppressor cells by releasing PGE2. Sci Rep. 2016;6:23824. doi:10.1038/srep23824. 9. Obermajer N, Muthuswamy R, Lesnock J, Edwards RP, Kalinski P. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood. 2011;118(20):5498-5505. 10. Miao J, Lu X, Hu Y, et al. Prostaglandin E and PD-1 mediated inhibition of antitumor CTL responses in the human tumor microenvironment. Oncotarget. 2017;8(52):89802-89810.