Involvement of the CD39/CD73/adenosine pathway in T-cell proliferation and NK cell-mediated antibody-dependent cell cytotoxicity in Sézary syndrome
Gabrielle Sonigo, Alizée Bozonnat, Maëlle Dumont, Nicolas Thonnart, Caroline Ram-Wolff, Adèle de Masson, Martine Bagot, Armand Bensussan, Anne Marie-Cardine
Abstract
Extracellular adenosine (eAdo) has been identified as a potent inhibitor of antitumor immune responses and enhancer of tumor survival. Two ectonucleotidases, CD39 and CD73, are involved in the generation of eAdo from adenosine triphosphate (ATP). Numerous studies have demonstrated their active role in promoting solid tumor outgrowth and spreading but also in inhibiting the antitumor immune response. Indeed, accumulation of eAdo was detected in solid tumors, and binding of eAdo to its receptors (A2AR) expressed at the surface of immune cells provides an immunosuppressive signal on effector T, natural killer (NK), and NKT cells, macrophages/dendritic cells, and neutrophils. 1 In addition, signaling through A2AR upregulates a number of antiinflammatory molecules and the activity of regulatory T cells, leading to a long-lasting immunosuppressive environment. ccordingly, the use of A2AR antagonists has demonstrated promising efficacy in the treatment of cancer. Anti-CD39 or anti-CD73 antibodies were also developed that efficiently block the hydrolysis of ATP into immune-suppressive eAdo and unleash antitumor immunity by stimulating dendritic cells and macrophages and restoring T-cell activation.