Fiche publication
Date publication
mai 2019
Journal
Cell reports
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BENSUSSAN Armand
Tous les auteurs :
Perrot I, Michaud HA, Giraudon-Paoli M, Augier S, Docquier A, Gros L, Courtois R, Déjou C, Jecko D, Becquart O, Rispaud-Blanc H, Gauthier L, Rossi B, Chanteux S, Gourdin N, Amigues B, Roussel A, Bensussan A, Eliaou JF, Bastid J, Romagné F, Morel Y, Narni-Mancinelli E, Vivier E, Paturel C, Bonnefoy N
Lien Pubmed
Résumé
Immune checkpoint inhibitors have revolutionized cancer treatment. However, many cancers are resistant to ICIs, and the targeting of additional inhibitory signals is crucial for limiting tumor evasion. The production of adenosine via the sequential activity of CD39 and CD73 ectoenzymes participates to the generation of an immunosuppressive tumor microenvironment. In order to disrupt the adenosine pathway, we generated two antibodies, IPH5201 and IPH5301, targeting human membrane-associated and soluble forms of CD39 and CD73, respectively, and efficiently blocking the hydrolysis of immunogenic ATP into immunosuppressive adenosine. These antibodies promoted antitumor immunity by stimulating dendritic cells and macrophages and by restoring the activation of T cells isolated from cancer patients. In a human CD39 knockin mouse preclinical model, IPH5201 increased the anti-tumor activity of the ATP-inducing chemotherapeutic drug oxaliplatin. These results support the use of anti-CD39 and anti-CD73 monoclonal antibodies and their combination with immune checkpoint inhibitors and chemotherapies in cancer.
Mots clés
CD39, CD73, adenosine pathway, cancer immunotherapies, immunosuppression, therapeutic antibodies, tumor micro-environment
Référence
Cell Rep. 2019 05 21;27(8):2411-2425.e9
