1-Methylnicotinamide is an immune regulatory metabolite in human ovarian cancer

Marisa K. Kilgour, Sarah MacPherson, Lauren G. Zacharias, Abigail E. Ellis, Ryan D. Sheldon, Elaine Y. Liu, Sarah Keyes, Brenna Pauly, Gillian Carleton, Bertrand Allard, Julian Smazynski, Kelsey S. Williams, Peter H. Watson, John Stagg, Brad H. Nelson, Ralph J. DeBerardinis, Russell G. Jones, Phineas T. Hamilton, Julian J. Lum

Research output: Contribution to journalArticlepeer-review

Abstract

Immune regulatory metabolites are key features of the tumor microenvironment (TME), yet with a few exceptions, their identities remain largely unknown. 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. Cells within the ascites and tumor had pervasive metabolite differences, with a notable enrichment in 1-methylnicotinamide (MNA) in T cells infiltrating the tumor compared with 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. Functionally, MNA induces T cells to secrete the tumor-promoting cytokine tumor necrosis factor alpha. Thus, TME-derived MNA contributes to the immune modulation of T cells and represents a potential immunotherapy target to treat human cancer.

Original languageEnglish (US)
Article numbereabe1174
JournalScience Advances
Volume7
Issue number4
DOIs
StatePublished - Jan 20 2021

ASJC Scopus subject areas

  • General

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