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      CD8 + T cells regulate tumor ferroptosis during cancer immunotherapy


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          Cancer immunotherapy restores and/or enhances effector function of CD8 + T cells in the tumor microenvironment 1, 2 . CD8 + T cells activated by cancer immunotherapy execute tumor clearance mainly by inducing cell death through perforin-granzyme- and Fas/Fas ligand-pathways 3, 4 . Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent lipid peroxide accumulation 5, 6 . Although it was mechanistically illuminated in vitro 7, 8 , emerging evidence has shown that ferroptosis may be implicated in a variety of pathological scenarios 9, 10 . However, the involvement of ferroptosis in T cell immunity and cancer immunotherapy is unknown. Here, we find that immunotherapy-activated CD8 + T cells enhance ferroptosis-specific lipid peroxidation in tumor cells, and in turn, increased ferroptosis contributes to the anti-tumor efficacy of immunotherapy. Mechanistically, interferon gamma (IFNγ) released from CD8 + T cells downregulates expression of SLC3A2 and SLC7A11, two subunits of glutamate-cystine antiporter system xc-, restrains tumor cell cystine uptake, and as a consequence, promotes tumor cell lipid peroxidation and ferroptosis. In preclinical models, depletion of cyst(e)ine by cyst(e)inase in combination with checkpoint blockade synergistically enhances T cell-mediated anti-tumor immunity and induces tumor cell ferroptosis. Expression of system xc- is negatively associated with CD8 + T cell signature, IFNγ expression, and cancer patient outcome. Transcriptome analyses before and during nivolumab therapy reveal that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNγ and CD8. Thus, T cell-promoted tumor ferroptosis is a novel anti-tumor mechanism. Targeting tumor ferroptosis pathway constitutes a therapeutic approach in combination with checkpoint blockade.

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          Most cited references10

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          A rapid method of total lipid extraction and purification.

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            ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.

            Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4-Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.
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              Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis.

              Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis-a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology, we discovered that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs on only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls-arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. Lipoxygenase (LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals, and tocopherols and tocotrienols (vitamin E) suppress LOX and protect against ferroptosis, suggesting a homeostatic physiological role for vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.

                Author and article information

                9 April 2019
                01 May 2019
                May 2019
                01 November 2019
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                [1 ]Department of Surgery, University of Michigan Roger Cancer Center
                [2 ]Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Roger Cancer Center
                [3 ]Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA
                [4 ]Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA
                [5 ]Michigan Center for Translational Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA
                [6 ]Cayman Chemical Company, 1180 East Ellsworth Rd, Ann Arbor MI 48108
                [7 ]Institute for Cancer Genetics, and Department of Pathology and Cell Biology, Columbia University Medical Center
                [8 ]Department of Gynecology & Obstetrics, University of Michigan School of Medicine, Ann Arbor, Michigan, USA
                [9 ]Department of Chemical Engineering, the University of Texas at Austin, TX, USA
                [10 ]Department of Molecular Biosciences, the University of Texas at Austin, TX, USA
                [11 ]Department of Computational Medicine & Bioinformatics, University of Michigan School of Medicine, Ann Arbor, Michigan, USA
                [12 ]Immunogenomics and Precision Oncology Platform, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY USA
                [13 ]Howard Hughes Medical Institute, University of Michigan School of Medicine, Ann Arbor, Michigan, USA
                [14 ]Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA
                [15 ]Graduate Program in Cancer Biology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA
                Author notes

                Author contributions W.W. and W.Z. conceived the project, designed the experiments and wrote the manuscript. W.W. performed most of the experiments with help from A.S., S.W., L.V. and W.S.. M.G. performed part of tumor immunotherapy experiments and data analysis. J.E.C., W.L., J.L., and M.C. performed bioinformatics analysis. M.G., P.D.K., and J.K.J. performed oxidized phospholipids analysis by LC-MS. P.L., H.X., J.Z., L.V., and H.Z. assisted with tumor xenograft experiments. I.K. assisted with flow cytometry analysis. C.L., Y.T., E.S., and G.G. contributed reagents. I.K., W.G., R.L., T.L., E.S., G.G., T.A.C., and A.C. contributed to discussions and edited the manuscript. W.Z. supervised work and acquired funding.

                Correspondence and requests for materials should be addressed to W.Z. ( wzou@ 123456med.umich.edu )

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