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

2021 ◽  
Vol 7 (4) ◽  
pp. eabe1174
Author(s):  
Marisa K. Kilgour ◽  
Sarah MacPherson ◽  
Lauren G. Zacharias ◽  
Abigail E. Ellis ◽  
Ryan D. Sheldon ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Modulation ◽  
Human Cancer ◽  
Serous Carcinoma ◽  
Necrosis Factor Alpha ◽  
Methyl Group ◽  
Cytokine Tumor Necrosis Factor ◽  
Factor Alpha ◽  
Immunotherapy Target ◽  
Necrosis Factor

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.

521 Immune regulatory metabolites in human ovarian cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A557-A557
Author(s):  
Julian Lum ◽  
Marisa Kilgour ◽  
Sarah MacPherson ◽  
Lauren Zacharias ◽  
Sarah Keyes ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Modulation ◽  
Human Cancer ◽  
Serous Carcinoma ◽  
Learning Tools ◽  
Necrosis Factor Alpha ◽  
University Of British Columbia ◽  
Cytokine Tumor Necrosis Factor ◽  
Immunotherapy Target ◽  
The University

BackgroundImmune 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.MethodsHere, 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.ResultsCells 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.ConclusionsOur 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 ApprovalThis study was approved by the University of British Columbia and BC Cancer Research Ethics Board (H07-00463).ConsentWritten 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.

scholarly journals Invariant Vα14 Chain NKT Cells Promote Plasmodium berghei Circumsporozoite Protein-Specific Gamma Interferon- and Tumor Necrosis Factor Alpha-Producing CD8+ T Cells in the Liver after Poxvirus Vaccination of Mice

2005 ◽  
Vol 73 (2) ◽  
pp. 849-858 ◽  
Author(s):  
Simone Korten ◽  
Richard J. Anderson ◽  
Carolyn M. Hannan ◽  
Eric G. Sheu ◽  
Robert Sinden ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Necrosis Factor ◽  
Plasmodium Berghei ◽  
Tumor Necrosis ◽  
Nkt Cells ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Necrosis Factor

ABSTRACT Understanding the protective mechanism in the liver induced by recombinant vaccines against the pre-erythrocytic stages of malaria is important for vaccine development. Most studies in mice have focused on splenic and peripheral blood T cells and identified gamma interferon (IFN-γ)-producing CD8+ T cells as correlates of protection, which can be induced by prime-boost vaccination with recombinant poxviruses. Invariant natural killer T (Vα14iNKT) cells can also protect against liver stage malaria, when activated, and are abundant in the liver. Since poxviruses have nonspecific immunomodulating effects, which are incompletely understood, we investigated whether recombinant poxviruses affect the protective properties of hepatic Vα14iNKT cells and thus vaccine efficacy. We show that intradermal vaccination with recombinant poxviruses activated Vα14iNKT cells and NK cells in the livers of BALB/c mice while inducing IFN-γ- and tumor necrosis factor alpha (TNF-α)-producing pre-erythrocytic stage antigen-specific CD8+ T cells. Greater numbers of hepatic Vα14iNKT cells secreted interleukin-4 than IFN-γ. Vaccinated Vα14iNKT-cell-deficient mice had lower, but still protective levels of hepatic and splenic IFN-γ+ and TNF-α+ CD8+ T cells and better protection rates later after challenge with Plasmodium berghei sporozoites. Therefore, vaccine-activated hepatic Vα14iNKT cells help in generating specific T cells but are not required for protection induced by recombinant poxviruses. Furthermore, double-positive INF-γ+/TNF-α+ CD8+ T cells were enriched in protected livers, suggesting that cells expressing both of these cytokines may be most relevant for protection.

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