Abstract PR01: Mitochondrial lactate metabolism in M2 macrophage polarization and ACL-dependent histone acetylation

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. Therefore, identifying dominant mechanisms that drive TAM polarization is needed to better understand M2-TAM biology and to identify more clinically efficacious TAM-directed immunotherapies. Highly glycolytic “Warburg” cancer cells produce lactate that independently drives naive M0→immunosuppressive M2 (M0→M2) macrophage polarization, but the mechanism(s) have not been fully elucidated. Metabolic-epigenetic links are increasingly being recognized as driving macrophage polarization. Because M0→M2 polarization induces metabolic reprogramming resulting in reduced glycolysis and increased mitochondrial metabolism/tricarboxylic acid (TCA) cycle activity we asked whether extracellular, tumor-derived lactate provides substrates for epigenetic modifications via the mitochondrial TCA cycle. Using a combination of gene expression assays, chromatin immunoprecipitation, and 13C-lactate isotope tracing metabolomics, we now show that macrophages undergoing M0→M2 polarization metabolize extracellular lactate to indirectly fuel ATP citrate lyase (ACL)-dependent histone acetylation. Specifically, our data shows that M2 macrophages incorporate exogenous lactate into the TCA cycle as pyruvate, which is then converted to citrate and exported for nucleo-cytoplasmic cleavage by ACL to generate acetyl-CoA necessary for histone acetylation. Inhibition of pyruvate import into the mitochondria or loss/inhibition of ACL attenuates lactate-induced M2 gene promoter histone acetylation, M2-specific gene expression and immunosuppressive effector functions. Importantly, the defects observed in lactate-dependent histone acetylation and M2 gene expression following loss/ inhibition of ACL or mitochondrial pyruvate uptake is fully reversed with exogenous acetate. In summary, these studies identify a novel functional role for extracellular lactate as a bona fide mitochondrial metabolite and indirect substrate for histone acetylation necessary to drive M2 TAM polarization. These results increase our understanding of the important metabolic relationship between lactate production/accumulation in “Warburg-like” tumor microenvironments and the resulting pro-tumorigenic properties of tumor infiltrating macrophages. Citation Format: Jordan T. Noe, Beatriz E. Rendon, Eun J. Kim, Samantha M. Morrissey, Anne E. Geller, Lindsey R. Conroy, Lyndsay E. Young, Ronald C. Bruntz, Hayley Affronti, Brian F. Clem, Jun Yan, Kathryn E. Wellen, Ramon C. Sun, Robert A. Mitchell. Mitochondrial lactate metabolism in M2 macrophage polarization and ACL-dependent histone acetylation [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PR01.