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

doi:10.1038/s41467-021-21804-1

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 journal › Article › peer-review

122 Citations (Scopus)

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 language	English
Article number	1455
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21804-1
Publication status	Published - Dec 2021
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-021-21804-1

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title = "Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma",

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.",

author = "Hung, {Man Hsin} and Lee, {Joo Sang} and Chi Ma and Diggs, {Laurence P.} and Sophia Heinrich and Chang, {Ching Wen} and Lichun Ma and Marshonna Forgues and Anuradha Budhu and Jittiporn Chaisaingmongkol and Mathuros Ruchirawat and Eytan Ruppin and Greten, {Tim F.} and Wang, {Xin Wei}",

note = "Publisher Copyright: {\textcopyright} 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",

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doi = "10.1038/s41467-021-21804-1",

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AU - Hung, Man Hsin

AU - Lee, Joo Sang

AU - Ma, Chi

AU - Diggs, Laurence P.

AU - Heinrich, Sophia

AU - Chang, Ching Wen

AU - Ma, Lichun

AU - Forgues, Marshonna

AU - Budhu, Anuradha

AU - Chaisaingmongkol, Jittiporn

AU - Ruchirawat, Mathuros

AU - Ruppin, Eytan

AU - Greten, Tim F.

AU - Wang, Xin Wei

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

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Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma

Abstract

ASJC Scopus subject areas

UN SDGs

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