Pharmacologic Screening Identifies Metabolic Vulnerabilities of CD8 + T Cells.

Autor:	Drijvers JM; Department of Immunology, Blavatnik Institute and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.; Department of Cell Biology, Blavatnik Institute and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts., Gillis JE; Department of Immunology, Blavatnik Institute and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts., Muijlwijk T; Department of Immunology, Blavatnik Institute and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts., Nguyen TH; Department of Immunology, Blavatnik Institute and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts., Gaudiano EF; Department of Immunology, Blavatnik Institute and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts., Harris IS; Department of Cell Biology, Blavatnik Institute and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts., LaFleur MW; Department of Immunology, Blavatnik Institute and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts., Ringel AE; Department of Cell Biology, Blavatnik Institute and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts., Yao CH; Department of Cell Biology, Blavatnik Institute and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts., Kurmi K; Department of Cell Biology, Blavatnik Institute and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts., Juneja VR; Department of Immunology, Blavatnik Institute and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts., Trombley JD; Department of Immunology, Blavatnik Institute and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts., Haigis MC; Department of Cell Biology, Blavatnik Institute and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts. arlene_sharpe@hms.harvard.edu marcia_haigis@hms.harvard.edu., Sharpe AH; Department of Immunology, Blavatnik Institute and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts. arlene_sharpe@hms.harvard.edu marcia_haigis@hms.harvard.edu.; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2021 Feb; Vol. 9 (2), pp. 184-199. Date of Electronic Publication: 2020 Dec 04.
DOI:	10.1158/2326-6066.CIR-20-0384
Abstrakt:	Metabolic constraints in the tumor microenvironment constitute a barrier to effective antitumor immunity and similarities in the metabolic properties of T cells and cancer cells impede the specific therapeutic targeting of metabolism in either population. To identify distinct metabolic vulnerabilities of CD8 + T cells and cancer cells, we developed a high-throughput in vitro pharmacologic screening platform and used it to measure the cell type-specific sensitivities of activated CD8 + T cells and B16 melanoma cells to a wide array of metabolic perturbations during antigen-specific killing of cancer cells by CD8 + T cells. We illustrated the applicability of this screening platform by showing that CD8 + T cells were more sensitive to ferroptosis induction by inhibitors of glutathione peroxidase 4 (GPX4) than B16 and MC38 cancer cells. Overexpression of ferroptosis suppressor protein 1 (FSP1) or cytosolic GPX4 yielded ferroptosis-resistant CD8 + T cells without compromising their function, while genetic deletion of the ferroptosis sensitivity-promoting enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4) protected CD8 + T cells from ferroptosis but impaired antitumor CD8 + T-cell responses. Our screen also revealed high T cell-specific vulnerabilities for compounds targeting NAD + metabolism or autophagy and endoplasmic reticulum (ER) stress pathways. We focused the current screening effort on metabolic agents. However, this in vitro screening platform may also be valuable for rapid testing of other types of compounds to identify regulators of antitumor CD8 + T-cell function and potential therapeutic targets. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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