VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors
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Open Access
- 19 January 2015
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 212 (2), 139-148
- https://doi.org/10.1084/jem.20140559
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.Keywords
This publication has 30 references indexed in Scilit:
- Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in CancerNew England Journal of Medicine, 2012
- Immune Inhibitory Molecules LAG-3 and PD-1 Synergistically Regulate T-cell Function to Promote Tumoral Immune EscapeCancer Research, 2012
- Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patientsJCI Insight, 2011
- Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunityThe Journal of Experimental Medicine, 2010
- Sunitinib Mediates Reversal of Myeloid-Derived Suppressor Cell Accumulation in Renal Cell Carcinoma PatientsClinical Cancer Research, 2009
- The VEGF-induced transcriptional response comprises gene clusters at the crossroad of angiogenesis and inflammationThrombosis and Haemostasis, 2009
- Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infectionNature Immunology, 2008
- Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesisNature, 2008
- Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGFPublished by American Society of Hematology ,2007
- Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cellsNature Medicine, 1996