CD8+ T cells regulate tumor ferroptosis during cancer immunotherapy

By Weimin Wang, Michael F. Green, J. E. Choi, M. Gijón, Paul D. Kennedy, Jeffrey K. Johnson, P. Liao, Xueting Lang, Ilona Kryczek, Amanda Sell and 20 more. Nature, 2019

2,406 citations recorded by the source corpus.

Cancer immunotherapy restores or enhances the effector function of CD8+ T cells in the tumour microenvironment1,2. CD8+ T cells activated by cancer immunotherapy clear tumours mainly by inducing cell death through perforin–granzyme and Fas–Fas ligand pathways3,4. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent accumulation of lipid peroxide5,6. Although it has been investigated in vitro7,8, there is emerging evidence that ferroptosis might be implicated in a variety of pathological scenarios9,10. It is unclear whether, and how, ferroptosis is involved in T cell immunity and cancer immunotherapy. Here we show that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumour cells, and that increased ferroptosis contributes to the anti-tumour efficacy of immunotherapy. Mechanistically, interferon gamma (IFNγ) released from CD8+ T cells downregulates the expression of SLC3A2 and SLC7A11, two subunits of the glutamate–cystine antiporter system xc−, impairs the uptake of cystine by tumour cells, and as a consequence, promotes tumour cell lipid peroxidation and ferroptosis. In mouse models, depletion of cystine or cysteine by cyst(e)inase (an engineered enzyme that degrades both cystine and cysteine) in combination with checkpoint blockade synergistically enhanced T cell-mediated anti-tumour immunity and induced ferroptosis in tumour cells. Expression of system xc− was negatively associated, in cancer patients, with CD8+ T cell signature, IFNγ expression, and patient outcome. Analyses of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNγ and CD8. Thus, T cell-promoted tumour ferroptosis is an anti-tumour mechanism, and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach. Interferon-γ induces ferroptotic cell death in tumours by suppressing cystine uptake and promoting lipid peroxidation.

Subfields: Immunology, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/951a297d36850a6c19b28fa297f923bf827d8fdb

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Citations in the corpus

Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis (2022, background): “The increased ferroptosis contributes to the antitumor efficacy of immunotherapy [56].”
Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. (2022, positive): “CD8 T cells have also been reported to exert a tumor-suppressive role through induction of ferroptosis in tumor cells; this activity is mediated by interferon gamma (IFNg) secretion from activated CD8 cells and results in tumor cell ferroptosis via downregulation of SLC7A11 (Wang et al., 2019).”
Ferroptosis in cancer therapy: a novel approach to reversing drug resistance (2022, background): “Recently, it has been shown that ferroptosis is involved in T cell immunity and cancer immunotherapy [52].”
The interaction between ferroptosis and lipid metabolism in cancer (2020, background): “Indeed, for the patients with nivolumab therapy, the clinical benefits are positively associated with reduced expression of SLC3A2 and increased IFNγ.(130) However, despite IFNγ is a wellknown antitumor cytokine, it also contributes to tumor escape under certain circumstances.”
Ferroptosis: mechanisms and links with diseases (2021, background): “Interestingly, IFN-γ can suppress the expression of SLC7A11A and SLC3A2, two essential proteins for the synthesis of GSH, leading to the transport deficit of cystine, which lipid peroxidation and ferroptosis in cancer.(189) Adaptive immunity is an indispensable and powerful ‘weapon’ in tumor immunit”