CD39 also critically contributes to the generation of extracellular adenosine from ATP as evidenced by the fact that deficiency of this enzyme results in significantly decreased adenosine content in tissues, not only at steady state, but also upon ischemia induction (80). Similar to studies with CD73-deficient mice, tumor growth and metastasis are reduced in CD39-null mice (391, 416). In addition, intraperitoneal delivery of a CD39 inhibitor in immunocompetent mice reduces tumor growth rates (391). Administration of an anti-CD39 mAb increased the survival of immuno-deficient mice inoculated with patient-derived tumors (390), indicating that CD39 can also promote tumor growth or metastasis in an immune system independent manner. In terms of mechanisms, several studies have demonstrated that in vitro inhibition of CD39 activity by pharmacologic inhibitors (45, 47, 62) or blocking mAbs (45, 417, 418) results in enhanced functionality of T cells (45, 47, 62, 418) and NK cells (45, 47, 418), as well as decreased Treg-mediated suppression of T cell proliferation (47, 417). Even though restriction of CD39 activity in vitro conclusively alleviates adenosine-induced immunosuppression, a surprisingly small number of studies demonstrate effectiveness of this approach within tumor-bearing mice. Finally, while humanized mAbs targeting CD39, such as IPH52 (Innate Pharma) have been developed, clinical studies exploring CD39 blockade/inhibition have not been launched.