Ex vivo activation of the GCN2 pathway metabolically reprograms T cells, leading to enhanced adoptive cell therapy

• DOI: 10.1016/j.xcrm.2024.101465
• Publication Date: 2024-03-08T15:39:34Z
• Authors: Michael St. Paul; Samuel D. Saibil; Meghan Kates; SeongJun Han; Scott C. Lien; Rob C. Laister; Kebria Hezaveh; Andreas Kloetgen; Susanne Penny; Tingxi Guo; Carlos Garcia-Batres; Logan K. Smith; Douglas C. Chung; Alisha R. Elford; Azin Sayad; Devanand Pinto; Tak W. Mak; Naoto Hirano; Tracy McGaha; Pamela S. Ohashi
• Keywords: Ex vivo; Cell therapy

The manipulation of T cell metabolism to enhance anti-tumor activity is an area active investigation. Here, we report that activating the amino acid starvation response in effector CD8+ cells ex vivo using general control non-depressible 2 (GCN2) agonist halofuginone (halo) enhances oxidative and function. Mechanistically, identified autophagy coupled with CD98-mTOR axis as key downstream mediators phenotype induced by halo treatment. adoptive transfer halo-treated into tumor-bearing mice led robust tumor curative responses. Halo-treated synergized a 4-1BB agonistic antibody growth mouse model resistant immunotherapy. Importantly, treatment human resulted similar metabolic functional reprogramming. These findings demonstrate GCN2 can activity.