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Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies #MMPMID26025381
Hossain F; Al-Khami AA; Wyczechowska D; Hernandez C; Zheng L; Reiss K; Del Valle L; Trillo-Tinoco J; Maj T; Zou W; Rodriguez PC; Ochoa AC
Cancer Immunol Res 2015[Nov]; 3 (11): 1236-47 PMID26025381show ga
Myeloid-derived suppressor cells (MDSC) promote tumor growth by inhibiting T-cell immunity and promoting malignant cell proliferation and migration. The therapeutic potential of blocking MDSCs in tumors has been limited by their heterogeneity, plasticity, and resistance to various chemotherapy agents. Recent studies have highlighted the role of energy metabolic pathways in the differentiation and function of immune cells; however, the metabolic characteristics regulating MDSCs remain unclear. We aimed to determine the energy metabolic pathway(s) used by MDSCs, establish its impact on their immunosuppressive function, and test whether its inhibition blocks MDSCs and enhances antitumor therapies. Using several murine tumor models, we found that tumor-infiltrating MDSCs (T-MDSC) increased fatty acid uptake and activated fatty acid oxidation (FAO). This was accompanied by an increased mitochondrial mass, upregulation of key FAO enzymes, and increased oxygen consumption rate. Pharmacologic inhibition of FAO blocked immune inhibitory pathways and functions in T-MDSCs and decreased their production of inhibitory cytokines. FAO inhibition alone significantly delayed tumor growth in a T cell-dependent manner and enhanced the antitumor effect of adoptive T-cell therapy. Furthermore, FAO inhibition combined with low-dose chemotherapy completely inhibited T-MDSCs immunosuppressive effects and induced a significant antitumor effect. Interestingly, a similar increase in fatty acid uptake and expression of FAO-related enzymes was found in human MDSCs in peripheral blood and tumors. These results support the possibility of testing FAO inhibition as a novel approach to block MDSCs and enhance various cancer therapies.