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

Autor:	St Paul M; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1C1, Canada., Saibil SD; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1C1, Canada. Electronic address: sam.saibil@uhn.ca., Kates M; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1C1, Canada., Han S; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1C1, Canada., Lien SC; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1C1, Canada., Laister RC; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada., Hezaveh K; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada., Kloetgen A; Department of Computational Biology of Infection Research, Helmholtz Centre for Infection Research, Braunschweig, Germany., Penny S; Human Health Therapeutics Research Centre, National Research Council Canada, Halifax, NS, Canada., Guo T; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1C1, Canada., Garcia-Batres C; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada., Smith LK; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada., Chung DC; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1C1, Canada., Elford AR; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada., Sayad A; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada., Pinto D; Human Health Therapeutics Research Centre, National Research Council Canada, Halifax, NS, Canada., Mak TW; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada., Hirano N; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1C1, Canada., McGaha T; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1C1, Canada., Ohashi PS; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1C1, Canada. Electronic address: pohashi@uhnresearch.ca.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2024 Mar 19; Vol. 5 (3), pp. 101465. Date of Electronic Publication: 2024 Mar 08.
DOI:	10.1016/j.xcrm.2024.101465
Abstrakt:	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. Competing Interests: Declaration of interests P.S.O. is on the SAB for Providence Therapeutics, Treadwell Therapeutics, and Egle Therapeutics and holds SRA with EMD Serono. The authors have filed a patent pertaining to the use of halo to enhance immunotherapy. (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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