Abstract 4277: EP601: Agonism of GPR84 activates myeloid cells and augments the response to anti-CTLA4 to promote tumor growth inhibition and prolong survival in a syngeneic (CT26) tumor model

Abstract GPR84 is a G-protein coupled receptor predominantly expressed on myeloid cells such as macrophages, NK cells, monocytes and neutrophils. It has previously been reported that GPR84 expression is induced by acute inflammatory stimuli and furthermore that GPR84 may be an interesting target to reverse the immunosuppressive tumor microenvironment1. In the current study, induced expression of GPR84 is confirmed as it is demonstrated that there is a 5-fold (or greater) expression of GPR84 on human (M1) macrophages polarized with either IFN-gamma or muramyl dipeptide-and-LPS (“MDP+LPS”). Compound A (CpdA) is a proprietary, selective, small-molecule agonist at GPR84 with similar potency at both the human and mouse GPR84 receptor orthologs (cAMP assay, EC50 = 13 nM and 9 nM, respectively). CpdA promotes TNF-alpha secretion from MDP+LPS-activated human macrophages in a concentration-dependent manner and this response is blocked by the GPR84 antagonist GLPG1205. The pharmacokinetic profile of CpdA has been established in rodents (t1/2 = 1h, oral bioavailability = 25%) and the compound is appropriate for in vivo testing. In the CT26 mouse tumor model, CpdA (30 mg/kg, PO, BID) significantly increased the response to anti-CLTA4 (2 mg/kg, IP, BIW) to >80% tumor growth inhibition and improved survival corresponding to altered immune cell infiltration into the tumor. These results demonstrate the potential of pharmacological activation of GPR84 as a novel approach relevant to cancer immunotherapy.1Li et al., Cancer Immunol Immunother (2024) Citation Format: Graeme L. Fraser, Catherine Sorlet, Nicolas Parmentier, Sarah Rorive, Guillaume Dutheuil. EP601: Agonism of GPR84 activates myeloid cells and augments the response to anti-CTLA4 to promote tumor growth inhibition and prolong survival in a syngeneic (CT26) tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4277.