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Published on: June 12, 2021
VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors
Thibault Voron1, Orianne Colussi1, Elie Marcheteau2
1INSERM U970, Paris Cardiovascular Research Center, Université Paris-Descartes, Sorbonne Paris Cité, 75015 Paris, France Service d'immunologie biologique, Service d'oncologie médicale, Service de chirurgie digestive, Service d'hépatogastroentérologie et d'oncologie digestive, Hôpital Européen Georges Pompidou, 75015 Paris, France.
Abstract:
Immune escape is a prerequisite for tumor development. To avoid the immune system, tumors develop different mechanisms, including T cell exhaustion, which is characterized by expression of immune inhibitory receptors, such as PD-1, CTLA-4, Tim-3, and a progressive loss of function. The recent development of therapies targeting PD-1 and CTLA-4 have raised great interest since they induced long-lasting objective responses in patients suffering from advanced metastatic tumors. However, the regulation of PD-1 expression, and thereby of exhaustion, is unclear. VEGF-A, a proangiogenic molecule produced by the tumors, plays a key role in the development of an immunosuppressive microenvironment. We report in the present work that VEGF-A produced in the tumor microenvironment enhances expression of PD-1 and other inhibitory checkpoints involved in CD8(+) T cell exhaustion, which could be reverted by anti-angiogenic agents targeting VEGF-A-VEGFR. In view of these results, association of anti-angiogenic molecules with immunomodulators of inhibitory checkpoints may be of particular interest in VEGF-A-producing tumors.
Insights
Tumor cells use VEGF-A to increase PD-1 expression on T cells, causing exhaustion. Anti-angiogenic therapies targeting VEGF-A can reverse this, suggesting combination treatments for cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Tumor immune escape is crucial for cancer development.
- T cell exhaustion, marked by inhibitory receptors like PD-1, leads to immune system evasion.
- Targeting PD-1 and CTLA-4 has shown promise in advanced metastatic cancers.
Purpose of the Study:
- To investigate the role of VEGF-A in regulating PD-1 expression and T cell exhaustion.
- To explore the potential of anti-angiogenic therapies in reversing immune suppression.
Main Methods:
- Analysis of VEGF-A's effect on PD-1 and other inhibitory checkpoint expression in the tumor microenvironment.
- Evaluation of anti-angiogenic agents targeting VEGF-A-VEGFR pathways.
Main Results:
- VEGF-A significantly enhances the expression of PD-1 and other inhibitory checkpoints in CD8(+) T cells.
- This enhancement contributes to T cell exhaustion within the tumor microenvironment.
- Anti-angiogenic agents targeting VEGF-A-VEGFR effectively reversed the upregulation of these checkpoints.
Conclusions:
- VEGF-A plays a key role in promoting T cell exhaustion by upregulating PD-1 and related checkpoints.
- Combining anti-angiogenic therapies with checkpoint inhibitors may be a promising strategy for VEGF-A-producing tumors.
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