Résumé
The CD39/ CD73/ adenosine pathway is an important regulator of effector immune cell response. We previously demonstrated that, in human cancer specimen, CD39 is expressed by infiltrating regulatory T cells, tumor cells and the tumor associated stroma. CD39 enzymatic activity decreases peritumoral ATP, a potent tumor cell toxicity and immunogenic inducer, and generates immunosuppressive adenosine that binds adenosine receptors and inhibits CD4, CD8 T cell and NK cell responses. We and other demonstrated that CD39-mediated decrease of extracellular ATP and increase of adenosine promote tumor progression and immune escape as well as resistance to chemotherapy-induced immune response. We therefore generated several CD39 blocking monoclonal antibodies and present here the latest developments of these antibodies. We provide evidence that CD39 blocking antibodies restore the proliferation of CD4 and CD8 T cells inhibited by melanoma cells expressing CD39 and increase the generation of CD8 cytotoxic T cells against CD39+ melanoma cells. We also demonstrated that CD39+ lymphoma cells are less sensitive to NK cell cytotoxic activity than CD39- lymphoma cells, and that CD39-blocking monoclonal antibodies increase NK-mediated lysis of CD39+ lymphoma cells but not CD39- lymphoma cells. In conclusion, CD39 blocking antibodies may represent a novel immunotherapy strategy for inhibiting regulatory T cells and tumor cell-mediated immunosuppression. The results presented here support the ongoing development of CD39 blocking monoclonal antibodies as potential anticancer drugs to restore antitumor immune response. Citation Format: Jeremy Bastid, Cécile Dejou, Jérôme Giustiniani, Stéphanie Cochaud, Gilles Alberici, Armand Bensussan, Jean-François Eliaou, Nathalie Bonnefoy. Blockade of the CD39 immunoregulatory pathway by monoclonal antibodies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5036. doi:10.1158/1538-7445.AM2014-5036