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J Exp Med. 2015 Feb 9;212(2):139-48. doi: 10.1084/jem.20140559. Epub 2015 Jan 19.

VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors.

Author information

1
INSERM 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.
2
INSERM U970, Paris Cardiovascular Research Center, Université Paris-Descartes, Sorbonne Paris Cité, 75015 Paris, France.
3
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.
4
Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
5
INSERM 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 julien.taieb@egp.aphp.fr.

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.

PMID:
25601652
PMCID:
PMC4322048
DOI:
10.1084/jem.20140559
[Indexed for MEDLINE]
Free PMC Article

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