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

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, Mayuresh M. Mane, Hong Zhong, Cailian Liu, Arnab Ghosh, Mohsen Abu-Akeel, Ellen Ackerstaff, Jason A. Koutcher, Ping-Chih Ho, Greg M. Delgoffe, Ronald Blasberg, Jedd D. Wolchok () and Taha Merghoub ()
Additional contact information
Roberta Zappasodi: Ludwig Collaborative and Swim Across America Laboratory, MSK
Inna Serganova: Weill Cornell Medicine
Ivan J. Cohen: Department of Neurology, MSK
Masatomo Maeda: Department of Neurology, MSK
Masahiro Shindo: Department of Neurology, MSK
Yasin Senbabaoglu: Ludwig Collaborative and Swim Across America Laboratory, MSK
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
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
Ping-Chih Ho: University of Lausanne
Greg M. Delgoffe: University of Pittsburgh
Ronald Blasberg: Department of Neurology, MSK
Jedd D. Wolchok: Ludwig Collaborative and Swim Across America Laboratory, MSK
Taha Merghoub: Ludwig Collaborative and Swim Across America Laboratory, MSK

Nature, 2021, vol. 591, issue 7851, 652-658

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03326-4

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