Prostaglandin E Receptor 4 Antagonist in Cancer Immunotherapy: Mechanisms of Action

Abstract

A highly expressed prostaglandin E 2 (PGE 2) in tumor tissues suppresses antitumor immunity in the tumor microenvironment (TME) and causes tumor immune evasion leading to disease progression. In animal studies, selective inhibition of the prostaglandin E receptor 4 (EP4), one of four PGE 2 receptors, suppresses tumor growth, restoring the tumor immune response toward an antitumorigenic condition. This review summarizes PGE 2 /EP4 signal inhibition in relation to the cancer-immunity cycle (C-IC), which describes fundamental tumor-immune interactions in cancer immunotherapy. PGE 2 is suggested to slow down C-IC by inhibiting natural killer cell functions, suppressing the supply of conventional dendritic cell precursors to the TME. This is critical for the tumor-associated antigen priming of CD8 + T cells and their translocation to the tumor tissue from the tumor-draining lymph node. Furthermore, PGE 2 activates several key immune-suppressive cells present in tumors and counteracts tumoricidal properties of the effector CD8 + T cells. These effects of PGE 2 drive the tumors to non-T-cell-inflamed tumors and cause refractory conditions to cancer immunotherapies, e.g., immune checkpoint inhibitor (ICI) treatment. EP4 antagonist therapy is suggested to inhibit the immune-suppressive and tumorigenic roles of PGE 2 in tumors, and it may sensitize the therapeutic effects of ICIs in patients with non-inflamed and C-IC-deficient tumors. This review provides insight into the mechanism of action of EP4 antagonists in cancer immunotherapy and suggests a C-IC modulating opportunity for EP4 antagonist therapy in combination with ICIs and/or other cancer therapies.

Eicosanoids in Cancer: Prostaglandin E2 Receptor 4 in Cancer Therapeutics and Immunotherapy

“…In cancer, the most abundant COX-2 product is prostaglandin E 2 (PGE 2 ) which binds four G-protein-coupled EP receptors (EP1-EP4) to activate several intracellular signaling pathways. EP4 is upregulated and contributes to the pathology of many human malignancies including those of the breast, prostate, colon, ovary, and lung (Reader et al, 2011;Majumder et al, 2018;Take et al, 2020). EP4 receptor signaling is linked to many properties of malignant cells including proliferation, migration, invasion, metastasis, angiogenesis, immune evasion, epithelial to mesenchymal transition, and cancer stem cell (CSC) properties.…”

“…There is growing evidence that EP4 represents a novel therapeutic target in cancer, both expressed on the malignant cell as well as on EP4-positive host cells. It is likely that EP4 antagonists would be used in combination with either cytotoxic therapies or with other immune-modulating strategies (for excellent reviews see Majumder et al, 2018;Take et al, 2020). There is growing evidence that EP4 blockade can reverse chemotherapy resistance in several tumor types and therefore combinations of EP4 antagonists with standard of care chemotherapy should be considered.…”

“…In support of future combination clinical trials, Albu et al showed that EP4 antagonism combined with either Treg depletion or with an antibody to CTLA-4 provided superior tumor control to either monotherapy (Albu et al, 2017). Cancer clinical trials to evaluate EP4 inhibitors are recruiting in trials of Grapiprant (ARY-007) in combination with pembrolizumab in subjects with either advanced MSS colorectal cancers (NCT03658772) or, in a separate trial in advanced NSCLC (NCT03696212) (Mizuno et al, 2019;Take et al, 2020). E7046 is being examined in a rectal cancer trial (NCT03152370) and BMS 986310 plus nivolumab is being investigated in a phase 1 trial in advanced solid tumors (NCT03661632).…”

Arachidonic acid metabolism controls macrophage alternative activation through regulating oxidative phosphorylation in PPARG dependent manner

“…Consistently, activating PPARG might be a potential mechanism of AA inhibiting M2 polarization. In addition, PGE2-EP4 signaling has been reviewed as a possible mechanism to M2 polarization (Take et al, 2020), while in our polarization model, we found PGE2 increased M2 polarization even though EP4…”

EP4 as a Therapeutic Target to Impede Breast Cancer-associated Angiogenesis and Lymphangiogenesis

“…Given the multiple tumor-promoting roles of EP4 expression on tumor cells and host immune cells and endothelial cells, we suggest that combination of EP4 antagonists and other immunomodulating drugs should work synergistically, especially in TNBCs displaying a diverse microenvironment. Excellent reviews by Fulton et al [139] and Take et al [140] strongly suggest the potential benefit of EP4 antagonist in combination with other immunomodulating agents in cancer therapy.…”