Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go?

Abstract

Cancer is a chronic disease and its pathogenesis is well correlated with infection and inflammation. Adenosine is a purine nucleoside, which is produced under metabolic stress like hypoxic conditions. Acute or chronic inflammatory conditions lead to the release of precursor adenine nucleotides (adenosine triphosphate (ATP), adenosien diphosphate (ADP) and adenosine monophosphate (AMP)) from cells, which are extracellularly catabolized into adenosine by extracellular ectonucleotidases, i.e., CD39 or nucleoside triphosphate dephosphorylase (NTPD) and CD73 or 5′-ectonucleotidase. It is now well-known that adenosine is secreted by cancer as well as immune cells during tumor pathogenesis under metabolic stress or hypoxia. Once adenosine is released into the extracellular environment, it exerts various immunomodulatory effects via adenosine receptors (A 1 , A 2A , A 2B , and A 3 ) expressed on various immune cells (i.e., macrophages, myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, dendritic cells (DCs), T cells, regulatory T cell (T regs ), etc.), which play very important roles in the pathogenesis of cancer. This review is intended to summarize the role of inflammation and adenosine in the immunopathogenesis of tumor along with regulation of tumor-specific immune response and its modulation as an adjunct approach to tumor immunotherapy.

The A3Adenosine Receptor: History and Perspectives

“…Indeed, ex vivo activation of CD8 + T cells with the A 3 AR agonist improves adoptive immunotherapy for melanoma (Montinaro et al, 2012). We emphasize that the identification of signal transduction pathways, through which adenosine exerts its inhibitory effects on cell-mediated antitumor immune responses, may allow for the development of focused pharmacologic strategies to reduce, or ablate, the impact of adenosinemediated immune suppression in cancer patients (Kumar, 2013).…”

Increased efficacy of a dendritic cell–based therapeutic cancer vaccine with adenosine receptor antagonist and CD73 inhibitor

“…8,9 The intracellular cAMP is known to be a highly immunosuppressive mediator. 3,10 Several studies also support the idea that adenosine stimulates the production of vascular endothelial growth factor (VEGF) and therefore supports tumor angiogenesis. [11][12][13] Adenosine in the tumor milieu is generated from extracellular nucleotides by ectonucleotidases such as CD39 and CD73.…”

Phenotypic and functional characteristics of CD39highhuman regulatory B cells (Breg)

“…On the other hand, the use of ADO by Treg for suppression of antitumor-reactive T cells in the tumor microenvironment represents a potentially important immunoregulatory mechanism operating in cancer. 20 Given the current data emphasizing the critical role of the B-cell presence in the immune signature of human tumors for outcome and responses to therapy, 21 the mechanisms B cells use to mediate suppression of antitumor responses are of primary interest. The major objective of this study was to further evaluate the phenotypic characteristics and functional roles of human activated CD39 C B cells producing 5 0 -AMP and ADO in regulating T lymphocyte responses.…”