Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma

Man Hsin Hung, Joo Sang Lee, Chi Ma, Laurence P. Diggs, Sophia Heinrich, Ching Wen Chang, Lichun Ma, Marshonna Forgues, Anuradha Budhu, Jittiporn Chaisaingmongkol, Mathuros Ruchirawat, Eytan Ruppin, Tim F. Greten and Xin Wei Wang ()
Additional contact information
Man Hsin Hung: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute
Joo Sang Lee: Cancer Data Science Lab, National Cancer Institute, National Institutes of Health
Chi Ma: Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Laurence P. Diggs: Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Sophia Heinrich: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute
Ching Wen Chang: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute
Lichun Ma: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute
Marshonna Forgues: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute
Anuradha Budhu: Liver Cancer Program, Center for Cancer Research, National Cancer Institute
Jittiporn Chaisaingmongkol: Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute
Mathuros Ruchirawat: Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute
Eytan Ruppin: Cancer Data Science Lab, National Cancer Institute, National Institutes of Health
Tim F. Greten: Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Xin Wei Wang: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21804-1

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