Related Experiment Video
Updated: Nov 17, 2025
Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice
Published on: June 12, 2021
CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours
Roberta Zappasodi1,2,3, Inna Serganova4,5, Ivan J Cohen5,6
1Ludwig Collaborative and Swim Across America Laboratory, MSK, New York, NY, USA. roz4002@med.cornell.edu.
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.
Insights
Blocking CTLA-4 enhances anti-tumour T cell responses, particularly in tumours with low glucose metabolism. This immunotherapy approach destabilizes regulatory T cells, improving treatment outcomes by reducing metabolic competition.
Area of Science:
- Immunology
- Cancer Biology
- Metabolic Regulation
Background:
- Metabolic competition within the tumour microenvironment can limit immunotherapy efficacy.
- CD28 signalling acts as a metabolic biosensor for T cells, while CTLA-4 engagement downregulates T cell glycolysis.
- Understanding the interplay between tumour metabolism and T cell function is crucial for enhancing cancer immunotherapy.
Purpose of the Study:
- To investigate the impact of CTLA-4 blockade on the metabolic fitness of intra-tumour T cells.
- To determine the relationship between CTLA-4 blockade, tumour cell glycolysis, and T cell responses.
- To elucidate the mechanism by which CTLA-4 blockade affects regulatory T cell stability in varying glycolytic environments.
Main Methods:
- Analysis of intra-tumour T cell metabolic fitness in relation to tumour cell glycolytic capacity.
- Treatment of mice bearing tumours with anti-CTLA-4 antibodies.
- In vitro mimicry of high and low glycolytic tumour microenvironments to assess T cell responses and regulatory T cell destabilization.
Main Results:
- CTLA-4 blockade enhanced T cell metabolic fitness and immune cell infiltration, especially in tumours with low glycolysis.
- Anti-CTLA-4 antibody treatment improved therapeutic outcomes in mice with glycolysis-defective tumours.
- Tumour-specific CD8+ T cell responses were associated with the destabilization of regulatory T cells in glycolysis-defective tumours.
Conclusions:
- Reducing tumour glucose competition can enhance the efficacy of CTLA-4 blockade immunotherapy.
- CTLA-4 blockade destabilizes regulatory T cells in a manner dependent on T cell glycolysis and CD28 signalling.
- Combining CTLA-4 blockade with tumour glycolysis inhibitors may represent a promising therapeutic strategy.
Related Concept Videos
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...