Epithelial Ovarian Cancer microenvironment regulates Myeloid cell metabolism to confer immunosuppression via glutamine metabolism.

Abstract

Abstract Myeloid Cells are a major constituent of epithelial ovarian cancer (EOC) microenvironment that confer immunosuppression and promote tumor growth. Using the syngeneic ID8 EOC model we show that its microenvironment is enriched in myeloid cell recruiting factors like GM-CSF, G-CSF, VEGF, TNF-a, IL-1b and IL-6. Tumor microenvironment (TME) exposed myeloid cells are highly immunosuppressive as seen by increased expression of CSF-R, S100a9, STAT-3, VEGF, TNF-a, iNOS, STAT-3 and T-cell suppression activity. TME exposed myeloid cells exhibited an activated metabolic phenotype that was fueled by glutamine dependent oxidative phosphorylation as assessed by XFe seahorse analyzer and targeted metabolomics. Deprivation of glutamine or use of a glutaminase inhibitor, BPTES reduced oxidative phosphorylation, decreased immunosuppressive markers and protected from T-cell suppression. Targeted energy metabolism gene expression arrays revealed that the mitochondrial enzyme, dihydrolipoamide succinyl transferase (DLST), a component of alpha-ketoglutarate dehydrogenase (a-KG) complex in TCA cycle, was elevated in TME exposed myeloid cells. Glutamine deprivation reduced DLST expression, suggesting that DLST expression is dependent on availability of glutamine. A novel small molecule inhibitor of a-KG complex, 3-methyl 2-oxalo valeric acid, regressed EOC growth, reversed myeloid cell energy phenotype and alleviated T-cell suppression. We propose that EOC induced expression of DLST metabolically regulates the immunosuppressive function of myeloid cells and targeting DLST may represent a new strategy to reduce immunosuppressive environment plaguing ovarian cancer.