Combination of EP 4 antagonist MF-766 and anti-PD-1 promotes anti-tumor efficacy by modulating both lymphocytes and myeloid cells.

Autor: Wang Y; Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA., Cui L; Department of Quantitative Biosciences, Merck & Co., Inc., Boston, Massachusetts, USA., Georgiev P; Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA., Singh L; Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA., Zheng Y; Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA., Yu Y; Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA., Grein J; Department of Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, Massachusetts, USA., Zhang C; Department of Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, Massachusetts, USA., Muise ES; Department of Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, Massachusetts, USA., Sloman DL; Department of Discovery Chemistry, Merck & Co., Inc., Boston, Massachusetts, USA., Ferguson H; Department of Pharmaceutical Science, Merck & Co., Inc., Boston, Massachusetts, USA., Yu H; Department of Pharmaceutical Science, Merck & Co., Inc., Boston, Massachusetts, USA., Pierre CS; Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA., Dakle PJ; Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA., Pucci V; Department of Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck & Co., Inc., Boston, Massachusetts, USA., Baker J; Department of Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck & Co., Inc., Boston, Massachusetts, USA., Loboda A; Department of Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, Massachusetts, USA., Linn D; Department of Quantitative Biosciences, Merck & Co., Inc., Boston, Massachusetts, USA., Brynczka C; Dept. Safety and Exploratory Pharmacology, Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., Boston, Massachusetts, USA., Wilson D; Department of Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, Massachusetts, USA., Haines BB; Department of Quantitative Biosciences, Merck & Co., Inc., Boston, Massachusetts, USA., Long B; Department of Quantitative Biosciences, Merck & Co., Inc., Boston, Massachusetts, USA., Wnek R; Department of Translational Biomarkers, Merck & Co., Inc., Boston, Massachusetts, USA., Sadekova S; Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA., Rosenzweig M; Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA., Haidle A; Department of Discovery Chemistry, Merck & Co., Inc., Boston, Massachusetts, USA., Han Y; Department of Discovery Chemistry, Merck & Co., Inc., Boston, Massachusetts, USA., Ranganath SH; Department of Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts, USA.
Jazyk: angličtina
Zdroj: Oncoimmunology [Oncoimmunology] 2021 Mar 18; Vol. 10 (1), pp. 1896643. Date of Electronic Publication: 2021 Mar 18.
DOI: 10.1080/2162402X.2021.1896643
Abstrakt: 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 (EP 1-4 ). 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 EP 4 receptor. EP 4 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)-α production in THP-1 cells and human blood, and PGE 2 -mediated inhibition of interleukin (IL)-2-induced interferon (IFN)-γ production in human NK cells. MF-766 reversed the inhibition of IFN-γ 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-γ, IL-2, and TNF-α production in primary histoculture and synergized with pembrolizumab in a PGE 2 high TME. Our studies demonstrate that the combination of EP 4 blockade with anti-PD-1 therapy enhances antitumor activity by differentially modulating myeloid cell, NK cell, cDC and T-cell infiltration profiles.
(© 2021 Merck and Co. Published with license by Taylor & Francis Group, LLC.)
Databáze: MEDLINE
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