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1-Methylnicotinamide is an immune regulatory metabolite in human ovarian cancer
Marisa K Kilgour1,2, Sarah MacPherson2, Lauren G Zacharias3
1Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada.
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.
Insights
Researchers identified 1-methylnicotinamide (MNA) as a key immune-regulatory metabolite in the tumor microenvironment (TME). MNA in T cells promotes tumor growth by inducing cytokine secretion, offering a potential immunotherapy target.
Area of Science:
- Oncology
- Immunology
- Metabolomics
Background:
- Immune regulatory metabolites within the tumor microenvironment (TME) are critical but largely unidentified.
- Understanding these metabolites is crucial for developing novel cancer therapies.
Purpose of the Study:
- To profile the metabolomes of tumor cells and T cells from high-grade serous carcinoma (HGSC) patients.
- To identify novel immune regulatory metabolites and their functional roles in the TME.
Main Methods:
- Comparative metabolomic profiling of T cells and tumor cells from ascites and solid tumors in HGSC patients.
- Analysis of nicotinamide N-methyltransferase (NNMT) expression in different cell types.
- Functional assays to assess the impact of 1-methylnicotinamide (MNA) on T cell cytokine production.
Main Results:
- Significant metabolite differences were observed between ascites and tumor compartments.
- 1-methylnicotinamide (MNA) was notably enriched in tumor-infiltrating T cells compared to ascites.
- NNMT expression was primarily found in fibroblasts and tumor cells, not T cells.
- MNA induced T cells to secrete tumor necrosis factor alpha (TNF-α), a pro-tumorigenic cytokine.
Conclusions:
- TME-derived MNA plays a role in modulating T cell immunity.
- MNA represents a potential therapeutic target for immunotherapy in human cancers.
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