Metabolic-epigenetic regulation of macrophage polarization.

Abstract

Tumor-associated macrophages polarized to an M2 phenotype (M2-TAMs) promote neo-angiogenesis, tumor-stromal matrix remodeling, and immuno-evasion, which, collectively, contribute to immunotherapeutic resistance and reduced cancer patient survival. Highly glycolytic “Warburg” cancer cells produce lactate that independently drives naïve M0→immunosuppressive M2 (M0→M2) macrophage polarization, but the mechanisms have not been fully elucidated. The atypical cytokine macrophage migration inhibitory factor (MIF) is a fundamental underlying requirement for immunosuppressive M2 macrophage polarization. Still, it is unknown whether a molecular link exists between lactate-supported and MIF-dependent M2 macrophage polarization. Using a combination of gene expression assays, chromatin immunoprecipitation, and metabolomic analyses, we identified that M2 macrophages incorporate exogenous lactate into the TCA cycle, with subsequent mitochondrial export as citrate and cleavage by ATP-citrate lyase (ACLY) to generate nucleo-cytosolic acetyl-CoA for histone acetylation. For the first time, our studies identify lactate as a bona fide mitochondrial metabolite in M2 macrophages that supports metabolic reprogramming and macrophage-mediated immunosuppression. These results enhance the understanding of the metabolic interplay between lactate-producing “Warburg-like” tumors and immunosuppressive macrophage phenotypes and may help identify molecular targets for the development of TAM-directed immunotherapies. Separately, we also identified that MIF is a critical determinant of metabolic reprogramming during M2 macrophage polarization by sustaining mitochondrial metabolism to support a metabolic-epigenetic link through α-ketoglutarate-dependent histone demethylation. Additionally, our data suggest that a CSN5/NRF2 pathway exists as an intermediary mechanistic link of MIF-dependent metabolic reprogramming during M2 macrophage polarization. These results suggest that small molecule MIF inhibition may be an efficacious immunotherapeutic strategy by targeting metabolic reprogramming during M2-TAM-mediated tumor progression. Altogether, the work described in this dissertation expands our knowledge of the metabolic-epigenetic regulations of M2 macrophage polarization by identifying the contribution of mitochondrial lactate metabolism in ACLY-dependent histone acetylation and by determining the contribution of MIF in metabolic reprogramming-dependent histone demethylation.