2019-05-01

University of Michigan researchers, in collaboration with Cayman Chemical, found that increased oxidized lipids in tumor cells lead to ferroptosis and with immunotherapy are linked to cancer cell death.

Weimin Wang, Michael Green, Jae Eun Choi, Miguel Gijón, Paul D. Kennedy, Jeffrey K. Johnson, Peng Liao, Xueting Lang, Ilona Kryczek, Amanda Sell, Houjun Xia, Jiajia Zhou, Gaopeng Li, Jing Li, Wei Li, Shuang Wei, Linda Vatan, Hongjuan Zhang, Wojciech Szeliga, Wei Gu, Rebecca Liu, Theodore S. Lawrence, Candice Lamb, Yuri Tanno, Marcin Cieslik, Everett Stone, George Georgiou, Timothy A. Chan, Arul Chinnaiyan, and Weiping Zou

Highlights

• Unexpected pathway for killing cancer cells linked to role of ferroptosis in cancer immunity
• Immunotherapy enhances oxidized lipids in tumor cells, which leads to ferroptosis
• Activated CD8⁺ T cells promote lipid peroxidation in tumor cells and sensitize tumors to ferroptosis inducers through IFNγ
• Ferroptosis sensitizers improve effectiveness of checkpoint inhibitor immunotherapy treatments in cancer cell lines and in mice bearing ovarian tumors
• Tumor cell ferroptosis presents potential mechanism by which CD8⁺ T cells mediate tumor clearance

Abstract

Cancer immunotherapy restores or enhances the effector function of CD8⁺ T cells in the tumour microenvironment. CD8⁺ T cells activated by cancer immunotherapy clear tumours mainly by inducing cell death through perforin-granzyme and Fas-Fas ligand pathways. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent accumulation of lipid peroxide. Although it has been investigated in vitro, there is emerging evidence that ferroptosis might be implicated in a variety of pathological scenarios. 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 x_c⁻, 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 x_c⁻ 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.

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Learn more about…

• Lipidomic Profiling Services
• Ferroptosis: A New Form of Cell Death