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

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 cells . By contrast, the engagement of CTLA-4 has b...

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Bibliographic Details
Published in:Nature (London) 2021-03, Vol.591 (7851), p.652
Main Authors: Zappasodi, Roberta, Serganova, Inna, Cohen, Ivan J, Maeda, Masatomo, Shindo, Masahiro, Senbabaoglu, Yasin, Watson, McLane J, Leftin, Avigdor, Maniyar, Rachana, Verma, Svena, Lubin, Matthew, Ko, Myat, Mane, Mayuresh M, Zhong, Hong, Liu, Cailian, Ghosh, Arnab, Abu-Akeel, Mohsen, Ackerstaff, Ellen, Koutcher, Jason A, Ho, Ping-Chih, Delgoffe, Greg M, Blasberg, Ronald, Wolchok, Jedd D, Merghoub, Taha
Format: Article
Language:English
Subjects:
Animals
Breast Neoplasms - immunology
Breast Neoplasms - metabolism
Cell Line, Tumor
CTLA-4 Antigen - antagonists & inhibitors
Female
Glycolysis
Humans
Melanoma - genetics
Melanoma - immunology
Melanoma - metabolism
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Neoplasms - immunology
Neoplasms - metabolism
T-Lymphocytes, Regulatory - immunology
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Summary: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 cells . By contrast, the engagement of CTLA-4 has been shown to downregulate T cell glycolysis . 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 (T ) 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 T cells is dependent on T 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 T cell function in the presence of glucose.
ISSN:1476-4687
DOI:10.1038/s41586-021-03326-4