 CD8+ T cells regulate tumour ferroptosis during cancer immunotherapyWeimin 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 ()
Nature, 2019, vol. 569, issue 7755, 270-274 Abstract: Abstract 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. Date: 2019 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:569:y:2019:i:7755:d:10.1038_s41586-019-1170-y Ordering information: This journal article can be ordered from DOI: 10.1038/s41586-019-1170-y Access Statistics for this article Nature is currently edited by Magdalena Skipper More articles in Nature from Nature |
Is your work missing from RePEc? Here is how to contribute.
Questions or problems? Check the EconPapers FAQ or send mail to .
EconPapers is hosted by the
School of Business at Örebro University.