Mitochondrial metabolism in tumor-associated macrophages: The role of MIF and tumor-derived lactate

Purpose: Within the tumor microenvironment, tumor-associated macrophages (TAMs) polarized to an phenotype promote angiogenesis, metastasis, and the suppression of anti-tumor immune responses. Previously, we have found that macrophage migration inhibitory factor (MIF) promotes lactate-enhanced M2-polarization, however the underlying mechanisms were not elucidated. As cancer cells that exhibit the Warburg Effect secrete copious amounts of lactate into the tumor microenvironment, highly glycolytic cancers may promote tumor progression by producing lactate to support an immunosuppressive tumor microenvironment. The goal of this study is to investigate the mechanism by which MIF and tumor-derived lactate support pro-tumorigenic M2-TAMs. Methods: Using primary bone marrow-derived macrophages (BMDMs), we explored the mechanisms of MIF and lactate-enhanced M2 polarization using metabolic inhibitors and gene expression assays. To investigate the role of MIF in mitochondrial metabolism, we conducted extracellular flux analysis to determine mitochondrial OCR and ECAR in macrophages polarized to an M0 and M2 phenotype. Results: Blocking mitochondrial pyruvate uptake reduces both M2 polarization and HIF1α stabilization. Blocking mitochondrial metabolism and respiration inhibits M2 polarization. MIF deficiency decreases mitochondrial OCR, NRF2 stability, and M2 polarization. Increasing CSN5 activity rescues the loss of M2 polarization with MIF deficiency. Conclusions: Tumor-derived lactate per se does not promote M2 polarization but instead requires subsequent metabolism to pyruvate. Additionally, we have identified that mitochondrial pyruvate metabolism is a previously undetermined requirement for M2 macrophages. Further, we have found a potential link between MIF and metabolism, where MIF likely regulates CSN5 activity and NRF2 stability to increase mitochondrial respiration. As inhibiting mitochondrial respiration blocks M2 polarization, MIF may promote lactate-enhanced M2 polarization by enhancing mitochondrial metabolism. Subsequent studies will be conducted to further investigate the metabolic pathways and mechanisms required for the mitochondrial metabolism of tumor-derived lactate in promoting M2-TAM polarization. Citation Format: Jordan Noe, Beatriz Rendon, Eun Jung Kim, Robert Mitchell. Mitochondrial metabolism in tumor-associated macrophages: The role of MIF and tumor-derived lactate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3783.