Medium-Chain Fatty Acid Receptor GPR84 Modulates Cytotoxic CD8 T-cell Antitumor Immunity through Metabolic Reprogramming

G protein-coupled receptor 84 (GPR84) is a medium-chain free fatty acid receptor predominantly expressed in myeloid cells. Previous studies have identified GPR84 as an enhancer of the pro-inflammatory myeloid cell responses and a regulator of metabolic homeostasis. However, the role of GPR84 in T-cell function and metabolism remains largely unexplored. This study tested the effect of GPR84 modulation on CD8+ T-cell function and metabolism in vitro and examined its effect on antitumor function in adoptive cellular therapy models. Pharmacologic antagonism with GLPG1205 or genetic deletion of GPR84 promoted T-cell differentiation, proliferation, cytokine production, and cytotoxicity, whereas agonism with DL175 reduced these functions. These functional changes were paralleled by changes in metabolic activity. Antagonism and genetic deletion increased glucose uptake, glycolysis, oxidative phosphorylation, and ATP production, which enhanced the overall cell energetic fitness, whereas agonism resulted in a quiescent energetic profile. Furthermore, antagonism or deletion of GPR84 in antigen-specific CD8+ T cells in adoptive cellular therapy models enhanced their antitumor effects in vivo. Thus, GPR84 inhibition improves CD8+ T-cell function and may further enhance adoptive cellular therapies.