Re-polarization of immunosuppressive macrophages to tumor-cytotoxic macrophages by repurposed metabolic drugs

Abstract

M2-like tumor-associated macrophages promote tumor progression by establishing an immunosuppressive tumor microenvironment. The phenotype and activity of immunosuppressive macrophages are related to their mitochondrial metabolism. Thus, we studied if drugs targeting mitochondrial metabolic pathways can repolarize macrophages from M2 into an M1-like phenotype or can prevent M0-to-M2 polarization. The drugs selected are clinically approved or in clinical trials and target M2-specific metabolic pathways: fatty acid oxidation (Perhexiline and Trimetazidine), glutaminolysis (CB-839), PPAR activation (HX531), and mitochondrial electron transport chain (VLX-600). Murine bone marrow-derived macrophages were either polarized to M2 using IL-4 in the presence of the drugs or polarized first into M2 and then treated with the drugs in presence of IFN-γ for re-polarization. Targeting both fatty acid oxidation with Perhexiline or the electron transport chain with VLX-600 in the presence of IFN-γ, impaired mitochondrial basal, and maximal respiration and resulted in M2 to M1-like re-polarization (increased iNOS expression, NO production, IL-23, IL-27, and TNF-α secretion), similar to LPS+IFN-γ re-polarization. Moreover, drug-induced macrophage re-polarization resulted in a strong tumor-cytotoxic activity. Furthermore, the polarization of M0-to M2-like macrophages was impaired by CB-839, Trimetazidine, HX531, and Perhexiline, while Hx531 and Perhexiline also reduced MCP-1 secretion. Our results show that by targeting cell metabolism, macrophages could be re-polarized from M2-into an anti-tumoral M1-like phenotype and that M0-to-M2 polarization could be prevented. Overall, this study provides rational for the use of clinically applicable drugs to change an immunosuppressive tumor environment into a proinflammatory tumor environment that could support cancer immunotherapies.

Dealing with Macrophage Plasticity to Address Therapeutic Challenges in Head and Neck Cancers

“…This metabolic plasticity is also a major feature found in macrophages. Classically, M1 capture their energy from glycolysis, fatty acid synthesis, and the pentose phosphate pathway, whereas M2 make extensive use of glutaminolysis and fatty acid oxidation to fuel oxidative phosphorylation [ 22 , 57 ]. A recent study reported that glutamine deprivation prevented IL-4 mediated polarization, highlighting the importance of glutaminolysis metabolism for M2 polarization [ 58 ].…”

NK cells and solid tumors: therapeutic potential and persisting obstacles

“…At least in preclinical CRC models, such an immunosuppressive pathway is initiated by the CAF-driven, CXCL8-dependent polarization of TAMs towards an M2-like phenotype [ 191 ]. M2-like TAMs collected from the ascites of patients with ovarian cancer and exposed to Toll-like receptor (TLR) ligands appear to undergo repolarization towards an M1-like state, resulting in IL12 secretion and acquisition of cytolytic functions by co-cultured NK cells [ 192 , 193 ]. Finally, monoclonal antibodies targeting scavenger receptors on M2-like TAMs have been shown to limit their immunosuppressive effects and efficiently derepress the cytolytic functions of NK cells in human and mouse models of melanoma [ 194 ].…”

Mechanism and strategies of immunotherapy resistance in colorectal cancer

“…Based on their polarization fate, they can be divided into the M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes. Interestingly, M1 and M2 cells can repolarize to each other depending on the interventions administered (for example, by targeting mitochondrial metabolic pathways) ( 41 – 43 ). Numerous studies have reported the supportive effects of TAMs on malignant cells in the CRC TME.…”