Extracellular ATP, other nucleotides and adenosine play critical, albeit often opposing roles in inflammation, immune regulation and tumor cell biology. As an example, ATP is associated with direct induction of tumor cell death and functions as a danger-associated molecular pattern molecule (DAMP) leading to the activation of innate and adaptive immune responses mediated via type-2 purinergic receptors. Hence, ATP once released into the extracellular compartment might create an immune-stimulatory tumor microenvironment that would favor tumor immunity. ATP and other nucleotides are, however, catalyzed to nucleoside derivatives (e.g. adenosine) by the ectonucleotidases CD39 and CD73, resulting in the activation of type-1 purinergic or adenosine receptors. Adenosine will suppress innate and adaptive immune responses and would be expected to foster an immune-suppressive tumor microenvironment favoring tumor growth, as well as potentially inducing chemoresistance.
The concepts addressed by the Robson laboratory and others, is that modulating the purinergic balance within the tumor microenvironment to promote ATP effects over those of Ado (“immunogenic purinergic modulation” via inhibition of CD39 and CD73) might be expected to enhance chemotherapy induced cytotoxicity, via elicitation of robust and persistent anti-tumor immunity.