Inhibition of T cell and natural killer cell function by adenosine and its contribution to immune evasion by tumor cells (Review).
The resistance of many human cancers to immune-based therapies, including adoptive immunotherapy and the administration of therapeutic cancer vaccines, has been attributed to tumor-associated immune suppression, due in part to immunosuppressive molecules located within the tumor microenvironment. Adenosine is a purine nucleoside found within the interstitial fluid of solid tumors at concentrations that are able to inhibit cell-mediated immune responses to tumor cells. It is well established that extracellular adenosine inhibits T lymphocyte activation and effector function, including T cell adhesion to tumor cells and cytotoxic activity, by signaling primarily through A2a and A3 adenosine receptors on the surface of T cells. Importantly, A2a adenosine receptor-deficient mice exhibit enhanced anti-tumor immune responses by CD8+ T cells, as well as a dramatic reduction in the growth of experimental tumors in comparison to wild-type controls. A2a adenosine receptor signaling has also been implicated in adenosine-mediated inhibition of cytokine production and cytotoxic activity by activated natural killer (NK) cells, although the process of NK cell granule exocytosis is apparently suppressed via a distinct and as yet uncharacterized adenosine receptor. In this report, we review the evidence that adenosine is a potent inhibitor of cellular immune responses and may therefore be a major barrier to the successful immunotherapy of human carcinomas. The signaling pathways through which adenosine exerts its inhibitory effects on cell-mediated immune responses are also discussed. The accumulated evidence suggests that the effectiveness of immune-based therapies for solid tumors may be enhanced by selective antagonism of the adenosine receptor subtypes through which adenosine inhibits the anti-tumor activity of T lymphocytes and NK cells.
Hoskin
David W
DW
Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada. d.w.hoskin@dal.ca
Mader
Jamie S
JS
Furlong
Suzanne J
SJ
Conrad
David M
DM
Blay
Jonathan
J
D000241:Adenosine / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D000243:Adenosine Deaminase / Q000378:metabolism / Q000502:physiology; D000818:Animals; D006801:Humans; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008954:Models, Biological; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D018047:Receptors, Purinergic P1 / Q000378:metabolism / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D019139:Tumor Escape / Q000187:drug effects*
D018047:Receptors, Purinergic P1; D000243:Adenosine Deaminase; D000241:Adenosine