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CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours
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CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours
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CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours
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Journal Article
CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours
2021
Overview
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
1
. By contrast, the engagement of CTLA-4 has been shown to downregulate T cell glycolysis
1
. 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
reg
) 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
reg
cells is dependent on T
reg
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
reg
cell function in the presence of glucose.
CTLA-4 promotes glucose uptake by tumour-infiltrating regulatory T cells, making them unstable.
