Abstract
T-cell exhaustion denotes a hypofunctional state of T lymphocytes commonly found in cancer, but how tumor cells drive T-cell exhaustion remains elusive. Here, we find T-cell exhaustion linked to overall survival in 675 hepatocellular carcinoma (HCC) patients with diverse ethnicities and etiologies. Integrative omics analyses uncover oncogenic reprograming of HCC methionine recycling with elevated 5-methylthioadenosine (MTA) and S-adenosylmethionine (SAM) to be tightly linked to T-cell exhaustion. SAM and MTA induce T-cell dysfunction in vitro. Moreover, CRISPR-Cas9-mediated deletion of MAT2A, a key SAM producing enzyme, results in an inhibition of T-cell dysfunction and HCC growth in mice. Thus, reprogramming of tumor methionine metabolism may be a viable therapeutic strategy to improve HCC immunity.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Biomarkers, Tumor
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CD8-Positive T-Lymphocytes
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CRISPR-Cas Systems
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Carcinogenesis / genetics
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Carcinogenesis / metabolism
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / immunology
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Carcinoma, Hepatocellular / metabolism*
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Carcinoma, Hepatocellular / pathology
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Cell Line, Tumor
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Female
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Gene Expression Regulation, Neoplastic
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Gene Knockout Techniques
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Humans
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Liver / metabolism
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Liver / pathology
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Liver Neoplasms / genetics
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Liver Neoplasms / immunology
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Liver Neoplasms / metabolism*
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Methionine / metabolism*
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Methionine Adenosyltransferase / blood
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Methionine Adenosyltransferase / genetics
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Methionine Adenosyltransferase / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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S-Adenosylmethionine / metabolism
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T-Lymphocytes / metabolism*
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Transcriptome
Substances
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Biomarkers, Tumor
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S-Adenosylmethionine
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Methionine
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Mat2a protein, mouse
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Methionine Adenosyltransferase