Ex vivo activation of the GCN2 pathway metabolically reprograms T cells, leading to enhanced adoptive cell therapy
Michael St. Paul, Samuel D. Saibil, Meghan Kates, SeongJun Han, Scott Lien, Rob C. Laister, Kebria Hezaveh, Andreas Kloetgen, Susanne Penny, Tingxi Guo, Carlos R. Garcia-Batres, Logan K. Smith, Douglas C. Chung, Alisha R. Elford, Azin Sayad, Devanand M. Pinto, Tak W. Mak, Naoto Hirano, Tracy L. McGaha, Pamela S. Ohashi
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 vivo using 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 vivo with 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.