TY - JOUR
T1 - Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma
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
N1 - Publisher Copyright:
© 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
PY - 2021/12/1
Y1 - 2021/12/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85102186720&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-21804-1
DO - 10.1038/s41467-021-21804-1
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C2 - 33674593
AN - SCOPUS:85102186720
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1455
ER -
