Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma
Man‐Hsin Hung, Joo Sang Lee, Chi Ma, Laurence P. Diggs, S. Heinrich, Ching-Wen Chang, Lichun Ma, Marshonna Forgues, Anuradha Budhu, Jittiporn Chaisaingmongkol, Mathuros Ruchirawat, Eytan Ruppin, Tim F. Greten, Xin Wei Wang
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.