Immune Regulatory Metabolites In Human Ovarian Cancer

Background Immune regulatory metabolites are key features of the tumor microenvironment (TME), yet with a few exceptions, their identities remain largely unknown. Importantly, little is known about the heterogeneity of metabolites that are present or absent in specimens from human tumors and immune compartments. Methods Here, we profiled tumor and T cells from tumor and ascites of patients with high-grade serous carcinoma (HGSC) to uncover the metabolomes of these distinct TME compartments. We devised a stringent and robust protocol to enrich cell populations from surgically resected samples in patients with HGSC. We conducted mass spectrometry-based analysis and developed machine learning tools to highlight novel metabolites that are present in different cellular lineages of the tumor. Results Cells within the ascites and tumor had pervasive metabolite differences, with a striking enrichment in 1-methylnicotinamide (MNA) in T cells infiltrating the tumor compared to ascites. Despite the elevated levels of MNA in T cells, the expression of nicotinamide N-methyltransferase, the enzyme that catalyzes the transfer of a methyl group from S-adenosylmethionine to nicotinamide, was restricted to fibroblasts and tumor cells. T cells treated with MNA stimulated secretion of the tumor promoting cytokine tumor necrosis factor alpha. Conclusions Our studies provide the first catalogue of metabolites in patient-derived tumors and T cells. We found that TME-derived MNA contributes to the immune modulation of T cells and represents a potential immunotherapy target to treat human cancer. Ethics Approval This study was approved by the University of British Columbia and BC Cancer Research Ethics Board (H07-00463). Consent Written informed consent was obtained from the patient to use the results of this study for educational purposes including publications. A copy of the written consent is on file and available for review by the Editor of this journal.