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

doi:10.1126/sciadv.abe1174

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

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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 language	English (US)
Article number	eabe1174
Journal	Science Advances
Volume	7
Issue number	4
DOIs	https://doi.org/10.1126/sciadv.abe1174
State	Published - Jan 20 2021

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Kilgour, M. K., MacPherson, S., Zacharias, L. G., Ellis, A. E., Sheldon, R. D., Liu, E. Y., Keyes, S., Pauly, B., Carleton, G., Allard, B., Smazynski, J., Williams, K. S., Watson, P. H., Stagg, J., Nelson, B. H., DeBerardinis, R. J., Jones, R. G., Hamilton, P. T., & Lum, J. J. (2021). 1-Methylnicotinamide is an immune regulatory metabolite in human ovarian cancer. Science Advances, 7(4), Article eabe1174. https://doi.org/10.1126/sciadv.abe1174

Kilgour, MK, MacPherson, S, Zacharias, LG, Ellis, AE, Sheldon, RD, Liu, EY, Keyes, S, Pauly, B, Carleton, G, Allard, B, Smazynski, J, Williams, KS, Watson, PH, Stagg, J, Nelson, BH, DeBerardinis, RJ, Jones, RG, Hamilton, PT & Lum, JJ 2021, '1-Methylnicotinamide is an immune regulatory metabolite in human ovarian cancer', Science Advances, vol. 7, no. 4, eabe1174. https://doi.org/10.1126/sciadv.abe1174

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title = "1-Methylnicotinamide is an immune regulatory metabolite in human ovarian cancer",

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.",

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

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AU - Zacharias, Lauren G.

AU - Ellis, Abigail E.

AU - Sheldon, Ryan D.

AU - Liu, Elaine Y.

AU - Keyes, Sarah

AU - Pauly, Brenna

AU - Carleton, Gillian

AU - Allard, Bertrand

AU - Smazynski, Julian

AU - Williams, Kelsey S.

AU - Watson, Peter H.

AU - Stagg, John

AU - Nelson, Brad H.

AU - DeBerardinis, Ralph J.

AU - Jones, Russell G.

AU - Hamilton, Phineas T.

AU - Lum, Julian J.

PY - 2021/1/20

Y1 - 2021/1/20

N2 - 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.

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

Abstract

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