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), [eabe1174]. https://doi.org/10.1126/sciadv.abe1174

1-Methylnicotinamide is an immune regulatory metabolite in human ovarian cancer. / Kilgour, Marisa K.; MacPherson, Sarah; Zacharias, Lauren G.; Ellis, Abigail E.; Sheldon, Ryan D.; Liu, Elaine Y.; Keyes, Sarah; Pauly, Brenna; Carleton, Gillian; Allard, Bertrand; Smazynski, Julian; Williams, Kelsey S.; Watson, Peter H.; Stagg, John; Nelson, Brad H.; DeBerardinis, Ralph J.; Jones, Russell G.; Hamilton, Phineas T.; Lum, Julian J.

In: Science Advances, Vol. 7, No. 4, eabe1174, 20.01.2021.

Research output: Contribution to journal › Article › peer-review

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

Kilgour, Marisa K. ; MacPherson, Sarah ; Zacharias, Lauren G. ; Ellis, Abigail E. ; Sheldon, Ryan D. ; Liu, Elaine Y. ; Keyes, Sarah ; Pauly, Brenna ; Carleton, Gillian ; Allard, Bertrand ; Smazynski, Julian ; Williams, Kelsey S. ; Watson, Peter H. ; Stagg, John ; Nelson, Brad H. ; DeBerardinis, Ralph J. ; Jones, Russell G. ; Hamilton, Phineas T. ; Lum, Julian J. / 1-Methylnicotinamide is an immune regulatory metabolite in human ovarian cancer. In: Science Advances. 2021 ; Vol. 7, No. 4.

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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.}",

note = "Funding Information: This work was supported by the research grants to J.J.L. from the U.S. Department of Defense Ovarian Cancer Research Program Pilot Award (W81XWH-18-1-0264) and Canadian Institutes of Health Research (MOP-142351 and PJT-162279). P.T.H. is supported by research grants from the Carraresi Family Foundation Award. B.H.N. is supported by research grants from the BC Cancer Foundation and the Canadian Foundation for Innovation. R.G.J. is supported by grants from the Canadian Institutes of Health Research (MOP-142259) and funds from the Van Andel Institute. M.K.K. is supported by a University of Victoria Graduate Award. P.T.H. is supported by a Canadian Institutes for Health Research Postdoctoral Fellowship. S.K. is supported by BioCanRx and BC Cancer scholarships. Biospecimens were obtained with assistance from the IROC-TTR Biobank. Single-cell library preparations and RNA sequencing were provided by Genome Quebec. P.T.H. is supported by research grants from the Carraresi Family Foundation Award. Carraresi Foundation OVCARE Research Grants are supported by the VGH & UBC Hospital Foundation. B.H.N. is supported by research grants from the BC Cancer Foundation and the Canadian Foundation for Innovation. Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved.",

year = "2021",

month = jan,

day = "20",

doi = "10.1126/sciadv.abe1174",

language = "English (US)",

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T1 - 1-Methylnicotinamide is an immune regulatory metabolite in human ovarian cancer

AU - Kilgour, Marisa K.

AU - MacPherson, Sarah

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.

N1 - Funding Information: This work was supported by the research grants to J.J.L. from the U.S. Department of Defense Ovarian Cancer Research Program Pilot Award (W81XWH-18-1-0264) and Canadian Institutes of Health Research (MOP-142351 and PJT-162279). P.T.H. is supported by research grants from the Carraresi Family Foundation Award. B.H.N. is supported by research grants from the BC Cancer Foundation and the Canadian Foundation for Innovation. R.G.J. is supported by grants from the Canadian Institutes of Health Research (MOP-142259) and funds from the Van Andel Institute. M.K.K. is supported by a University of Victoria Graduate Award. P.T.H. is supported by a Canadian Institutes for Health Research Postdoctoral Fellowship. S.K. is supported by BioCanRx and BC Cancer scholarships. Biospecimens were obtained with assistance from the IROC-TTR Biobank. Single-cell library preparations and RNA sequencing were provided by Genome Quebec. P.T.H. is supported by research grants from the Carraresi Family Foundation Award. Carraresi Foundation OVCARE Research Grants are supported by the VGH & UBC Hospital Foundation. B.H.N. is supported by research grants from the BC Cancer Foundation and the Canadian Foundation for Innovation. Publisher Copyright: Copyright © 2021 The Authors, some rights reserved.

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.

AB - 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

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