Inhibiting fatty acid oxidation blocks the immunosuppressive functions of myeloid-derived suppressor cells and enhances cancer therapies (TUM6P.960)

Abstract

Abstract Myeloid-derived suppressor cells (MDSC) promote tumor growth by inhibiting T cell immunity through various mechanisms including the depletion of arginine and the production of nitric oxide and peroxinitrites. Blocking of any single mechanism has only moderate therapeutic effects because MDSC show high adaptability and upregulate the remaining suppressive pathways. We studied whether disrupting the energy metabolic pathway(s) of MDSC would modulate their immunosuppressive functions and enhance antitumor effects. Using several murine tumor models, we found that tumor-infiltrating MDSC (T-MDSC) increased fatty acid uptake and activated fatty acid oxidation (FAO). This was accompanied by increased mitochondrial mass and function, key FAO enzymes, and oxygen consumption rate. These metabolic changes paralleled with the induction of immunosuppressive mechanisms. Inhibition of FAO blocked immunosuppressive mechanisms and functions in T-MDSC and decreased their production of immunosuppressive cytokines. Interestingly, it also diminished the number of regulatory T cells and resulted in a T cell-dependent decrease in tumor growth. FAO inhibition also significantly increased antitumor effects with low-dose chemotherapy or cellular immunotherapy. Human MDSC demonstrated similar characteristics. These data support the possibility of testing FAO inhibition as a novel approach to block MDSC and enhance various cancer therapies. *F. Hossain and A.A. Al-Khami contributed equally to this work.