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, Xin Wei Wang

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number1455
JournalNature Communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021
Externally publishedYes

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