On the mechanism of anti-CD39 immune checkpoint therapy

Abstract

With the coming of age of cancer immunotherapy, the search for new therapeutic targets has led to the identification of immunosuppressive adenosine as an important regulator of antitumor immunity. This resulted in the development of selective inhibitors targeting various components of the adenosinergic pathway, including small molecules antagonists targeting the high affinity A2A adenosine receptor and low affinity A2B receptor, therapeutic monoclonal antibodies (mAbs) and small molecules targeting CD73 and therapeutic mAbs targeting CD39. As each regulator of the adenosinergic pathway present non-overlapping biologic functions, a better understanding of the mechanisms of action of each targeted approach should accelerate clinical translation and improve rational design of combination treatments. In this review, we discuss the potential mechanisms-of-action of anti-CD39 cancer therapy and potential toxicities that may emerge from sustained CD39 inhibition. Caution should be taken, however, in extrapolating data from gene-targeted mice to patients treated with blocking anti-CD39 agents. As phase I clinical trials are now underway, further insights into the mechanism of action and potential adverse events associated with anti-CD39 therapy are anticipated in coming years.

Keywords: A2A; CD39; CD73; adenosine; checkpoint blockade; immune checkpoint; immunotherapy.

Figure 1

CD39 in the tumor immunity cycle. CD39 expression in tumors, lymph nodes and vasculature impacts tumor immunity in various intertwined ways. (1) CD39 suppresses NLRP3 inflammasome activation and pyroptosis induced by P2X7 receptor. (2) CD39 impairs immunogenic cell death and tumor antigen presentation by DCs by depleting ATP and increasing extracellular adenosine levels (3). During T cell priming, CD39 inhibits costimulatory ATP signals and increases adenosine-mediated immunosuppression. (4) CD39 expression on endothelial cells regulates transendothelial migration of immune cells and promotes angiogenesis. (5) CD39 expression on stromal cells favors fibroblasts barrier function and immunosuppression. (6) CD39 expression and activity is associated with dysfunctional T cells and NK cells, ‘M2’-like macrophages and promotes immunosuppression by T regulatory cells (Tregs), myeloid cells and B cell-derived microvesicles. DCs, dendritic cells; MDSCs, myeloid-derived suppressor cells; NK, natural killer.