Extracellular vesicles in cancer immune responses: roles of purinergic receptors

Extracellular vesicles (EVs) are nano- to micro-scale membrane-enclosed vesicles that are released from presumably all cell types. Tumor cells and immune cells are prodigious generators of EVs often with competing phenotypes in terms of immune suppression versus immune stimulation. Purinergic receptors, proteins that bind diverse purine nucleotides and nucleosides (ATP, ADP, AMP, adenosine), are widely expressed across tissues and cell types, and are prominent players in immune and tumor cell nucleotide metabolism. The effects of purinergic receptor stimulation or agonism tend to produce inflammatory responses that may aid immune stimulation but may also provoke various immune suppression mechanisms, particularly in the tumor microenvironment. EVs released by cells following receptor stimulation are frequently pro-inflammatory, but often also pro-thrombolytic; these EVs may generate an environment that favors tumor progression at the cost of an effective immune response. Purinergic signaling pathways are becoming more recognized as valuable targets in various therapeutic scenarios, including cancer. It is possible that some of those clinically relevant compounds might also impact EV secretion and/or phenotype, which would hopefully capitalize on the immune stimulatory properties of purinergic signaling while minimizing the immune suppressive consequences. This review covers a relatively understudied area in EV biology, but even so, focuses almost exclusively on the purinergic receptors in a very limited capacity. There is much more to evaluate and incorporate into our understanding of extracellular nucleotides in EV biology, and we hope this work prompts further discovery.