학술논문
Ex vivoactivation of the GCN2 pathway metabolically reprograms T cells, leading to enhanced adoptive cell therapy
Document Type
Article
Author
St. Paul, Michael; Saibil, Samuel D.; Kates, Meghan; Han, SeongJun; Lien, Scott C.; Laister, Rob C.; Hezaveh, Kebria; Kloetgen, Andreas; Penny, Susanne; Guo, Tingxi; Garcia-Batres, Carlos; Smith, Logan K.; Chung, Douglas C.; Elford, Alisha R.; Sayad, Azin; Pinto, Devanand; Mak, Tak W.; Hirano, Naoto; McGaha, Tracy; Ohashi, Pamela S.
Source
Cell Reports Medicine; March 2024, Vol. 5 Issue: 3
Subject
Language
ISSN
26663791
Abstract
The manipulation of T cell metabolism to enhance anti-tumor activity is an area of active investigation. Here, we report that activating the amino acid starvation response in effector CD8+T cells ex vivousing the general control non-depressible 2 (GCN2) agonist halofuginone (halo) enhances oxidative metabolism and effector function. Mechanistically, we identified autophagy coupled with the CD98-mTOR axis as key downstream mediators of the phenotype induced by halo treatment. The adoptive transfer of halo-treated CD8+T cells into tumor-bearing mice led to robust tumor control and curative responses. Halo-treated T cells synergized in vivowith a 4-1BB agonistic antibody to control tumor growth in a mouse model resistant to immunotherapy. Importantly, treatment of human CD8+T cells with halo resulted in similar metabolic and functional reprogramming. These findings demonstrate that activating the amino acid starvation response with the GCN2 agonist halo can enhance T cell metabolism and anti-tumor activity.