Inhibition of Medium-Chain Fatty Acid Receptor GPR84 Enhances Metabolism, Cytotoxicity and Anti-Tumor Function of CD8 T cells
GPR84 is a medium-chain free fatty acid receptor predominately expressed on myeloid cells. Previous studies identified GPR84 as an enhancer of pro-inflammatory myeloid cell response and a regulator of metabolic homeostasis. However, the role of GPR84 on T cell function and metabolism remains wholly unexplored. This study tested the effect of GPR84 modulation on CD8+ T cell function and metabolism in vitro, and examined its effect on anti-tumor function in adoptive cellular therapy models. Inhibition of GPR84 with the antagonist GLPG1205 promoted CD8+ T cell differentiation, proliferation, cytokine production, and cytotoxicity. This effect was confirmed using CRISPR-Cas9 GPR84 deleted CD8+ T cells. In contrast, treatment with the GPR84 agonist DL175 inhibited proliferation, cytokine production and cytotoxicity. These functional changes were paralleled by changes in metabolic activity. GPR84 antagonist GLPG1205 increased glucose uptake, glycolysis, oxidative phosphorylation (OXPHOS) and ATP production, which enhanced the energetic fitness of CD8+ T cells. Furthermore, stimulation of antigen-specific CD8+ T cells with GPR84 antagonist in vitro, or deletion of GPR84 in antigen specific T cells before adoptive cellular therapy resulted in a significantly enhanced anti-tumor effect in vivo. This study is the first demonstration that GPR84 modulation in T cells can enable more effectively killing of tumor cells and reduce tumor growth, and opens a novel approach to significantly enhance the efficacy of adoptive cellular therapies including CAR-T, TIL or CAR-NK cells. Overall design: Cells (T cells and bone marrow-derived MDSC) were treated with GPR84 agonist or antagonist for 48h and the RNA was extracted to determine the effect on gene expression on each cell type