Combination of EP4 antagonist MF-766 and anti-PD-1 promotes anti-tumor efficacy by modulating both lymphocytes and myeloid cells

Prostaglandin E-2 (PGE(2)), an arachidonic acid pathway metabolite produced by cyclooxygenase (COX)-1/2, has been shown to impair anti-tumor immunity through engagement with one or more E-type prostanoid receptors (EP1-4). Specific targeting of EP receptors, as opposed to COX-1/2 inhibition, has been proposed to achieve preferential antagonism of PGE(2)-mediated immune suppression. Here we describe the anti-tumor activity of MF-766, a potent and highly selective small-molecule inhibitor of the EP4 receptor. EP4 inhibition by MF-766 synergistically improved the efficacy of anti-programmed cell death protein 1 (PD-1) therapy in CT26 and EMT6 syngeneic tumor mouse models. Multiparameter flow cytometry analysis revealed that treatment with MF-766 promoted the infiltration of CD8(+) T cells, natural killer (NK) cells and conventional dendritic cells (cDCs), induced M1-like macrophage reprogramming, and reduced granulocytic myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME). In vitro experiments demonstrated that MF-766 restored PGE(2)-mediated inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha production in THP-1 cells and human blood, and PGE(2)-mediated inhibition of interleukin (IL)-2-induced interferon (IFN)-gamma production in human NK cells. MF-766 reversed the inhibition of IFN-gamma in CD8(+) T-cells by PGE(2) and impaired suppression of CD8(+) T-cells induced by myeloid-derived suppressor cells (MDSC)/PGE(2.) In translational studies using primary human tumors, MF-766 enhanced anti-CD3-stimulated IFN-gamma, IL-2, and TNF-alpha production in primary histoculture and synergized with pembrolizumab in a PGE(2) high TME. Our studies demonstrate that the combination of EP4 blockade with anti-PD-1 therapy enhances antitumor activity by differentially modulating myeloid cell, NK cell, cDC and T-cell infiltration profiles.

Automated summary

The study demonstrates that the EP4 inhibitor MF-766 synergizes with anti-PD-1 therapy to enhance anti-tumor activity by modulating infiltration profiles of myeloid cells, NK cells, cDCs, and T-cells in the tumor microenvironment (TME).