title: Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies.
abstract: 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 MDSC 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 MDSC remain unclear. We aimed to determine the energy metabolic pathway(s) used by MDSC, establish its impact on their immunosuppressive function, and test whether its inhibition blocks MDSC and enhances antitumor therapies. 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 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-MDSC 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-MDSC 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 MDSC in peripheral blood and tumors. These results support the possibility of testing FAO inhibition as a novel approach to block MDSC and enhance various cancer therapies.
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana. Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Fokhrul
authors.initials: F
authors.lastname: Hossain
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Amir A
authors.initials: AA
authors.lastname: Al-Khami
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Dorota
authors.initials: D
authors.lastname: Wyczechowska
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Claudia
authors.initials: C
authors.lastname: Hernandez
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Liqin
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana. Department of Internal Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Krzystoff
authors.initials: K
authors.lastname: Reiss
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana. Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Luis Del
authors.initials: LD
authors.lastname: Valle
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Jimena
authors.initials: J
authors.lastname: Trillo-Tinoco
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Maj
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan.
authors.forename: Weiping
authors.initials: W
authors.lastname: Zou
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana. Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Rodriguez
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana. Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, Louisiana. aochoa@lsuhsc.edu.
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Ochoa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000975:Antioxidants / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D003131:Combined Modality Therapy; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004734:Energy Metabolism / Q000276:immunology; D004852:Epoxy Compounds / Q000627:therapeutic use; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology*; D010084:Oxidation-Reduction / Q000187:drug effects; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D004852:Epoxy Compounds; D005227:Fatty Acids; C054207:etomoxir