Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor

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Live regulatory T cells (Treg cells) suppress antitumor immunity, but how Treg cells behave in the metabolically abnormal tumor microenvironment remains unknown. Here we show that tumor Treg cells undergo apoptosis, and such apoptotic Treg cells abolish spontaneous and PD-L1-blockade-mediated antitumor T cell immunity. Biochemical and functional analyses show that adenosine, but not typical suppressive factors such as PD-L1, CTLA-4, TGF-β, IL-35, and IL-10, contributes to apoptotic Treg-cell-mediated immunosuppression. Mechanistically, apoptotic Treg cells release and convert a large amount of ATP to adenosine via CD39 and CD73, and mediate immunosuppression via the adenosine and A2A pathways. Apoptosis in Treg cells is attributed to their weak NRF2-associated antioxidant system and high vulnerability to free oxygen species in the tumor microenvironment. Thus, the data support a model wherein tumor Treg cells sustain and amplify their suppressor capacity through inadvertent death via oxidative stress. This work highlights the oxidative pathway as a metabolic checkpoint that controls Treg cell behavior and affects the efficacy of therapeutics targeting cancer checkpoints.

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This work was supported (in part) by the US National Institutes of Health (grants CA217540, CA123088, CA099985, CA156685, CA171306, CA190176, CA193136, CA211016, and 5P30CA46592 to W.Z.), the Ovarian Cancer Research Fund, and the Marsha Rivkin Center for Ovarian Cancer Research (W.Z.; I.K.). We are grateful to L. Carter and X. Hu for critical discussions about the A2A pathway. We thank D. Postiff, M. Vinco, R. Craig, and J. Barikdar at the Tissue and Molecular Pathology Core for their assistance. We thank C. Ruan and S. Bridges at the Metabolomics Core for their support. Cd274−/− mice and Pdcd1−/− mice were provided by L. Chen (Yale University, New Haven, Connecticut, USA) and T. Honjo (Kyoto University, Kyoto, Japan), respectively.

Author information

Author notes

    • Tomasz Maj
    •  & Wei Wang

    These authors contributed equally to this work.


  1. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.

    • Tomasz Maj
    • , Wei Wang
    • , Joel Crespo
    • , Hongjuan Zhang
    • , Weimin Wang
    • , Shuang Wei
    • , Linda Vatan
    • , Irene Shao
    • , Wojciech Szeliga
    • , Ilona Kryczek
    •  & Weiping Zou
  2. Department of Immunology and Key Laboratory of Medical Immunology of the Ministry of Public Health, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.

    • Wei Wang
  3. Rackham Graduate School, University of Michigan, Ann Arbor, Michigan, USA.

    • Joel Crespo
    •  & Weiping Zou
  4. Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.

    • Weimin Wang
    •  & J Rebecca Liu
  5. Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.

    • Lili Zhao
  6. Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.

    • Costas Lyssiotis
  7. The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.

    • Costas Lyssiotis
    •  & Weiping Zou
  8. Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.

    • Weiping Zou


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T.M., Wei Wang, I.K., and W.Z. designed the experiments. T.M., I.K., and W.Z. wrote the paper. Wei Wang, T.M., J.C., S.W., L.V., and I.K. performed the in vivo tumor experiments. L.V., W.S., I.K., and J.R.L. provided and processed clinical specimens and performed immunohistochemical and pathological analysis. T.M., Wei Wang, H.Z., I.S., and Weimin Wang performed the immunological and biochemical assays. I.K., L.Z., T.M., C.L., Wei Wang and W.Z. analyzed data.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Weiping Zou.

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