CD73 generation of immunosuppressive adenosine within the hypoxic tumor microenvironment causes dysregulation of immune cell infiltrates, resulting in tumor progression, metastases, and poor disease outcomes. Therapies targeted toward the adenosinergic pathway, such as antibodies targeting CD73 and CD39, have proven efficacy in mouse tumor models; however, humanized versions are only in preliminary development. In contrast, A2A adenosine receptor antagonists have progressed to late-stage clinical trials in Parkinson disease, yet evidence of their role in oncology is limited. Mark J. Smyth et al. compare the merits and challenges of these therapeutic approaches, identifying tumor indications and combinations that may be fruitful as they progress to the clinic.

High concentrations of immunosuppressive adenosine have been reported in cancers, and adenosine is implicated in the growth of tumors. Release of extracellular ATP in the hypoxic tumor microenvironment is converted to adenosine by CD39 and CD73 ectonucleotidases. CD39 and CD73 are broadly expressed across a number of cell types. Modulation of their distribution can vary dependent on cellular activation and tissue localization. Adenosine enhances polarization of myeloid and T-cell subsets to proangiogenic and immunosuppressive phenotypes, enhancing tumor growth and survival. High adenosine levels affect effector immune cells, NK cells, and CD8+ T cells, responsible for cytotoxic killing of aberrant malignancies due to inhibited expression of molecules that mediate cell death. DC, dendritic cells; IDO, indoleamine 2,3 dioxygenase; TCR, T-cell receptor.

Reference:

Targeting Cancer-Derived Adenosine:New Therapeutic Approaches. Cancer Discovery. 2014;4(8):879-88