Pharmacologic Screening Identifies Metabolic Vulnerabilities of CD8+ T Cells

作者：Jefte M. Drijvers, Jacob E. Gillis, Tara Muijlwijk, Thao H Nguyen, Emily F. Gaudiano, I. Harris, M. LaFleur, A. Ringel, Cong-Hui Yao, Kiran Kurmi, Vikram R. Juneja, Justin D. Trombley, M. Haigis, A. Sharpe · 发表于：Cancer immunology research · 年份：2020 · DOI：10.1158/2326-6066.cir-20-0384 · 被引用次数：147 · 研究领域：Biology、Medicine

It is challenging to develop metabolism-targeted therapeutics because T cells and cancer cells have similar metabolic properties. The authors develop an in vitro pharmacologic screening platform and highlight ferroptosis as a metabolic vulnerability of CD8+ T cells. 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 reveale...