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

被引:941
作者
Voron, Thibault [1 ,4 ]
Colussi, Orianne [1 ,5 ]
Marcheteau, Elie [1 ]
Pernot, Simon [1 ,5 ]
Nizard, Mevyn [1 ]
Pointet, Anne-Laure [1 ,5 ]
Latreche, Sabrina [1 ]
Bergaya, Sonia [1 ]
Benhamouda, Nadine [2 ]
Tanchot, Corinne [1 ]
Stockmann, Christian [1 ]
Combe, Pierre [3 ]
Berger, Anne [4 ]
Zinzindohoue, Franck [4 ]
Yagita, Hideo [6 ]
Tartour, Eric [1 ,2 ]
Taieb, Julien [1 ,5 ]
Terme, Magali [1 ]
机构
[1] Univ Paris 05, Paris Cardiovasc Res Ctr, Sorbonne Paris Cite, INSERM,U970, F-75015 Paris, France
[2] Hop Europeen Georges Pompidou, Serv Immunol Biol, F-75015 Paris, France
[3] Hop Europeen Georges Pompidou, Serv Oncol Med, F-75015 Paris, France
[4] Hop Europeen Georges Pompidou, Serv Chirurg Digest, F-75015 Paris, France
[5] Hop Europeen Georges Pompidou, Serv Hepatogastroenterol & Oncol Digest, F-75015 Paris, France
[6] Juntendo Univ, Sch Med, Dept Immunol, Tokyo 1138421, Japan
关键词
ENDOTHELIAL GROWTH-FACTOR; DIRECTLY SUPPRESSES ACTIVATION; TYROSINE KINASE INHIBITOR; CHRONIC VIRAL-INFECTION; RECEPTOR-TYPE; IMMUNE SUPPRESSION; CARCINOMA PATIENTS; CANCER PATIENTS; OVARIAN-CANCER; EXHAUSTION;
D O I
10.1084/jem.20140559
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:139 / 148
页数:10
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