CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy

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 GuRebecca Liu, Theodore S. Lawrence, Candice Lamb, Yuri Tanno, Marcin Cieslik, Everett Stone, George Georgiou, Timothy A. Chan, Arul Chinnaiyan, Weiping Zou

Research output: Contribution to journalLetter

25 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)270-274
Number of pages5
JournalNATURE
Volume569
Issue number7755
DOIs
StatePublished - May 9 2019

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Immunotherapy
T-Lymphocytes
Neoplasms
Cystine
Interferon-gamma
Lipid Peroxidation
Cysteine
Immunity
Cell Death
Antiporters
Gene Expression Profiling
Cysts
Down-Regulation
Iron
Apoptosis
Ligands
Lipids

ASJC Scopus subject areas

  • General

Cite this

Wang, W., Green, M., Choi, J. E., Gijón, M., Kennedy, P. D., Johnson, J. K., ... Zou, W. (2019). CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. NATURE, 569(7755), 270-274. https://doi.org/10.1038/s41586-019-1170-y

CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. / Wang, Weimin; Green, Michael; Choi, Jae Eun; Gijón, Miguel; Kennedy, Paul D.; Johnson, Jeffrey K.; Liao, Peng; Lang, Xueting; Kryczek, Ilona; Sell, Amanda; Xia, Houjun; Zhou, Jiajia; Li, Gaopeng; Li, Jing; Li, Wei; Wei, Shuang; Vatan, Linda; Zhang, Hongjuan; Szeliga, Wojciech; Gu, Wei; Liu, Rebecca; Lawrence, Theodore S.; Lamb, Candice; Tanno, Yuri; Cieslik, Marcin; Stone, Everett; Georgiou, George; Chan, Timothy A.; Chinnaiyan, Arul; Zou, Weiping.

In: NATURE, Vol. 569, No. 7755, 09.05.2019, p. 270-274.

Research output: Contribution to journalLetter

Wang, W, Green, M, Choi, JE, Gijón, M, Kennedy, PD, Johnson, JK, Liao, P, Lang, X, Kryczek, I, Sell, A, Xia, H, Zhou, J, Li, G, Li, J, Li, W, Wei, S, Vatan, L, Zhang, H, Szeliga, W, Gu, W, Liu, R, Lawrence, TS, Lamb, C, Tanno, Y, Cieslik, M, Stone, E, Georgiou, G, Chan, TA, Chinnaiyan, A & Zou, W 2019, 'CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy', NATURE, vol. 569, no. 7755, pp. 270-274. https://doi.org/10.1038/s41586-019-1170-y
Wang W, Green M, Choi JE, Gijón M, Kennedy PD, Johnson JK et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. NATURE. 2019 May 9;569(7755):270-274. https://doi.org/10.1038/s41586-019-1170-y
Wang, Weimin ; Green, Michael ; Choi, Jae Eun ; Gijón, Miguel ; Kennedy, Paul D. ; Johnson, Jeffrey K. ; Liao, Peng ; Lang, Xueting ; Kryczek, Ilona ; Sell, Amanda ; Xia, Houjun ; Zhou, Jiajia ; Li, Gaopeng ; Li, Jing ; Li, Wei ; Wei, Shuang ; Vatan, Linda ; Zhang, Hongjuan ; Szeliga, Wojciech ; Gu, Wei ; Liu, Rebecca ; Lawrence, Theodore S. ; Lamb, Candice ; Tanno, Yuri ; Cieslik, Marcin ; Stone, Everett ; Georgiou, George ; Chan, Timothy A. ; Chinnaiyan, Arul ; Zou, Weiping. / CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. In: NATURE. 2019 ; Vol. 569, No. 7755. pp. 270-274.
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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.",
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AU - Wang, Weimin

AU - Green, Michael

AU - Choi, Jae Eun

AU - Gijón, Miguel

AU - Kennedy, Paul D.

AU - Johnson, Jeffrey K.

AU - Liao, Peng

AU - Lang, Xueting

AU - Kryczek, Ilona

AU - Sell, Amanda

AU - Xia, Houjun

AU - Zhou, Jiajia

AU - Li, Gaopeng

AU - Li, Jing

AU - Li, Wei

AU - Wei, Shuang

AU - Vatan, Linda

AU - Zhang, Hongjuan

AU - Szeliga, Wojciech

AU - Gu, Wei

AU - Liu, Rebecca

AU - Lawrence, Theodore S.

AU - Lamb, Candice

AU - Tanno, Yuri

AU - Cieslik, Marcin

AU - Stone, Everett

AU - Georgiou, George

AU - Chan, Timothy A.

AU - Chinnaiyan, Arul

AU - Zou, Weiping

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N2 - 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.

AB - 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.

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