1. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors
- Author
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Elie Marcheteau, Mevyn Nizard, Hideo Yagita, Eric Tartour, Pierre Combe, Corinne Tanchot, Sabrina Latreche, Thibault Voron, Nadine Benhamouda, Julien Taieb, Franck Zinzindohoué, Magali Terme, Anne-Laure Pointet, Sonia Bergaya, Christian Stockmann, Orianne Colussi, Anne Berger, and Simon Pernot
- Subjects
Vascular Endothelial Growth Factor A ,T cell ,Programmed Cell Death 1 Receptor ,Immunology ,CD8-Positive T-Lymphocytes ,Biology ,Inhibitory postsynaptic potential ,Mice ,Lymphocytes, Tumor-Infiltrating ,Immune system ,Neoplasms ,medicine ,Animals ,Immunology and Allergy ,Cytotoxic T cell ,CTLA-4 Antigen ,Loss function ,Tumor microenvironment ,Gene Expression Profiling ,Brief Definitive Report ,food and beverages ,Cell biology ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,Vascular endothelial growth factor A ,Receptors, Vascular Endothelial Growth Factor ,medicine.anatomical_structure ,Female ,CD8 ,Protein Binding ,Signal Transduction - Abstract
VEGF-A production in the tumor microenvironment enhances expression of PD-1 and other inhibitory checkpoints involved with CD8+ T cell exhaustion, which can be reversed with anti-VEGF/VEGFR treatment., 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.
- Published
- 2015
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