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CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours

Author

Listed:
  • Roberta Zappasodi

    (Ludwig Collaborative and Swim Across America Laboratory, MSK
    Parker Institute for Cancer Immunotherapy, MSK
    Weill Cornell Medicine)

  • Inna Serganova

    (Weill Cornell Medicine
    Department of Neurology, MSK)

  • Ivan J. Cohen

    (Department of Neurology, MSK
    Gerstner Sloan Kettering Graduate School of Biomedical Sciences, MSK)

  • Masatomo Maeda

    (Department of Neurology, MSK)

  • Masahiro Shindo

    (Department of Neurology, MSK)

  • Yasin Senbabaoglu

    (Ludwig Collaborative and Swim Across America Laboratory, MSK
    Genentech)

  • McLane J. Watson

    (University of Pittsburgh)

  • Avigdor Leftin

    (Department of Medical Physics, MSK)

  • Rachana Maniyar

    (Ludwig Collaborative and Swim Across America Laboratory, MSK)

  • Svena Verma

    (Ludwig Collaborative and Swim Across America Laboratory, MSK
    Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine)

  • Matthew Lubin

    (Department of Neurology, MSK)

  • Myat Ko

    (Department of Neurology, MSK)

  • Mayuresh M. Mane

    (Department of Neurology, MSK)

  • Hong Zhong

    (Ludwig Collaborative and Swim Across America Laboratory, MSK)

  • Cailian Liu

    (Ludwig Collaborative and Swim Across America Laboratory, MSK)

  • Arnab Ghosh

    (Ludwig Collaborative and Swim Across America Laboratory, MSK)

  • Mohsen Abu-Akeel

    (Ludwig Collaborative and Swim Across America Laboratory, MSK)

  • Ellen Ackerstaff

    (Department of Medical Physics, MSK)

  • Jason A. Koutcher

    (Weill Cornell Medicine
    Department of Medical Physics, MSK
    MSK
    MSK)

  • Ping-Chih Ho

    (University of Lausanne
    University of Lausanne)

  • Greg M. Delgoffe

    (University of Pittsburgh)

  • Ronald Blasberg

    (Department of Neurology, MSK
    MSK)

  • Jedd D. Wolchok

    (Ludwig Collaborative and Swim Across America Laboratory, MSK
    Parker Institute for Cancer Immunotherapy, MSK
    Weill Cornell Medicine
    MSK)

  • Taha Merghoub

    (Ludwig Collaborative and Swim Across America Laboratory, MSK
    Parker Institute for Cancer Immunotherapy, MSK
    Weill Cornell Medicine
    MSK)

Abstract

Limiting metabolic competition in the tumour microenvironment may increase the effectiveness of immunotherapy. Owing to its crucial role in the glucose metabolism of activated T cells, CD28 signalling has been proposed as a metabolic biosensor of T cells1. By contrast, the engagement of CTLA-4 has been shown to downregulate T cell glycolysis1. Here we investigate the effect of CTLA-4 blockade on the metabolic fitness of intra-tumour T cells in relation to the glycolytic capacity of tumour cells. We found that CTLA-4 blockade promotes metabolic fitness and the infiltration of immune cells, especially in glycolysis-low tumours. Accordingly, treatment with anti-CTLA-4 antibodies improved the therapeutic outcomes of mice bearing glycolysis-defective tumours. Notably, tumour-specific CD8+ T cell responses correlated with phenotypic and functional destabilization of tumour-infiltrating regulatory T (Treg) cells towards IFNγ- and TNF-producing cells in glycolysis-defective tumours. By mimicking the highly and poorly glycolytic tumour microenvironments in vitro, we show that the effect of CTLA-4 blockade on the destabilization of Treg cells is dependent on Treg cell glycolysis and CD28 signalling. These findings indicate that decreasing tumour competition for glucose may facilitate the therapeutic activity of CTLA-4 blockade, thus supporting its combination with inhibitors of tumour glycolysis. Moreover, these results reveal a mechanism by which anti-CTLA-4 treatment interferes with Treg cell function in the presence of glucose.

Suggested Citation

  • Roberta Zappasodi & Inna Serganova & Ivan J. Cohen & Masatomo Maeda & Masahiro Shindo & Yasin Senbabaoglu & McLane J. Watson & Avigdor Leftin & Rachana Maniyar & Svena Verma & Matthew Lubin & Myat Ko , 2021. "CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours," Nature, Nature, vol. 591(7851), pages 652-658, March.
  • Handle: RePEc:nat:nature:v:591:y:2021:i:7851:d:10.1038_s41586-021-03326-4
    DOI: 10.1038/s41586-021-03326-4
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    Citations

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    Cited by:

    1. Nils-Petter Rudqvist & Maud Charpentier & Claire Lhuillier & Erik Wennerberg & Sheila Spada & Caroline Sheridan & Xi Kathy Zhou & Tuo Zhang & Silvia C. Formenti & Jennifer S. Sims & Alicia Alonso & Sa, 2023. "Immunotherapy targeting different immune compartments in combination with radiation therapy induces regression of resistant tumors," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    2. Xinyu Tang & Xinrui Mao & Peiwen Ling & Muxin Yu & Hua Pan & Jiaming Wang & Mingduo Liu & Hong Pan & Wen Qiu & Nan Che & Kai Zhang & Feifan Bao & Hongwei Peng & Qiang Ding & Shui Wang & Wenbin Zhou, 2024. "Glycolysis inhibition induces anti-tumor central memory CD8+T cell differentiation upon combination with microwave ablation therapy," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Xijiao Ren & Zhuo Cheng & Jinming He & Xuemei Yao & Yingqi Liu & Kaiyong Cai & Menghuan Li & Yan Hu & Zhong Luo, 2023. "Inhibition of glycolysis-driven immunosuppression with a nano-assembly enhances response to immune checkpoint blockade therapy in triple negative breast cancer," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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