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PMID: 31043744 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy.

Nature ·Vol. 569 ·No. 7755 ·2019-00-00 ·Pages 270-274

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

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.

MeSH Terms
Amino Acid Transport System y+/metabolism Animals B7-H1 Antigen/antagonists & inhibitors CD8-Positive T-Lymphocytes/immunology Cell Line, Tumor Cysteine/metabolism Female Ferroptosis/drug effects Fusion Regulatory Protein 1, Heavy Chain/metabolism Humans Immunotherapy Interferon-gamma/immunology Lipid Peroxidation Melanoma/genetics,immunology,metabolism,therapy Mice Neoplasms/immunology,metabolism,therapy Nivolumab/therapeutic use Reactive Oxygen Species/metabolism Treatment Outcome
Chemicals
Amino Acid Transport System y+ B7-H1 Antigen CD274 protein, human Fusion Regulatory Protein 1, Heavy Chain IFNG protein, human Reactive Oxygen Species SLC3A2 protein, human SLC7A11 protein, human Nivolumab Interferon-gamma Cysteine
Authors & Affiliations
30 authors, click to expand affiliations / ORCID
Wang Weimin
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Green Michael
Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Choi Jae Eun
Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Michigan Center for Translational Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Gijón Miguel
Cayman Chemical Company, Ann Arbor, MI, USA.
Kennedy Paul D
Cayman Chemical Company, Ann Arbor, MI, USA.
Johnson Jeffrey K
Cayman Chemical Company, Ann Arbor, MI, USA.
Liao Peng
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Lang Xueting
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Kryczek Ilona
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Sell Amanda
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Xia Houjun
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Zhou Jiajia
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Li Gaopeng
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Li Jing
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Li Wei
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Wei Shuang
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Vatan Linda
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Zhang Hongjuan
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Szeliga Wojciech
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Gu Wei
Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Liu Rebecca
Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Lawrence Theodore S
Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Lamb Candice
Department of Chemical Engineering, University of Texas at Austin, Austin, TX, USA. | Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.
Tanno Yuri
Department of Chemical Engineering, University of Texas at Austin, Austin, TX, USA. | Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.
Cieslik Marcin
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Department of Computational Medicine & Bioinformatics, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Stone Everett
Department of Chemical Engineering, University of Texas at Austin, Austin, TX, USA. | Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.
Georgiou George
Department of Chemical Engineering, University of Texas at Austin, Austin, TX, USA. | Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.
Chan Timothy A
Immunogenomics and Precision Oncology Platform, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Chinnaiyan Arul
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Michigan Center for Translational Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA. | Howard Hughes Medical Institute, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Zou Weiping
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. wzou@med.umich.edu. | Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA. wzou@med.umich.edu. | Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA. wzou@med.umich.edu. | Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI, USA. wzou@med.umich.edu. | Graduate Program in Cancer Biology, University of Michigan School of Medicine, Ann Arbor, MI, USA. wzou@med.umich.edu.
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/s41586-019-1170-y
Email
wzou@med.umich.edu
Published
2019-00-00
Epub
2019-00-01
Pages
270-274
Language
English
Region
England
NLM ID
0410462
PMCID
PMC6533917
Subset
IM
Grants
NCI NIH HHS · P30 CA046592 · United States
NCI NIH HHS · R01 CA189623 · United States
NCI NIH HHS · R01 CA152470 · United States
NCI NIH HHS · P30 CA008748 · United States
NCI NIH HHS · R01 CA193136 · United States
NCI NIH HHS · CA189623 · United States
NCI NIH HHS · R01 CA123088 · United States
NCI NIH HHS · R01 CA217510 · United States
NCI NIH HHS · CA205426 · United States
NCI NIH HHS · R01 CA190176 · United States
NCI NIH HHS · R01 CA214911 · United States
NCI NIH HHS · R01 CA127648 · United States
NCI NIH HHS · R35 CA232097 · United States
NCI NIH HHS · R01 CA099985 · United States
NCI NIH HHS · R01 CA211016 · United States
Corrections
CommentIn
PMID: 31113802
CommentIn
PMID: 31160718
CommentIn
PMID: 31269423
External Links
PubMed source DOI: 10.1038/s41586-019-1170-y PMC Full Text View journal details
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