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Sorrentino et al. Role of A 2B receptor in cancer

in some patho-physiological conditions, including under inflammatory-hypoxic conditions, its expression
vascular injury, chronic lung disease, vascular is up-regulated while the concentration of adenosine
[68]
[69]
leak, and ischemic disease. First studies reaches highest levels. In this context, the A receptor
[70]
[71]
2B
performed by Ryzhov et al. in 2008 show that tumor may play an important role in mediating adenosine-
[72]
growth in A receptor deficient mice was reduced induced pathological effects.
2B
compared to that observed in wild type mice, providing
the first genetic evidence for a pivotal role of A A RECEPTOR AND TUMOR IMMUNITY
2B
receptor in tumor progression. 2B
Although the role of A receptor in controlling T-cell-
2B
Up to now a number of selective A receptor mediated response is not completely clear, compelling
2B
antagonists (such as MRS1754, ATL801, GS-6201, evidence indicate that this receptor may influence the
PSB603 and PSB1115) and selective A agonists features of some immune cell populations.
2B
(Bay60-6583) have been synthesized, helping the
study and the characterization of the role of this It has been demonstrated that A receptor is involved
2B
adenosine receptor in many patho-physiological in the differentiation of T cells under Treg skewing-
conditions, including cancer, as discussed below. conditions, since its inhibition is able to suppress the
expression of FoxP3 and IL-10 production in a way
EXPRESSION OF A RECEPTOR completely independent from T cell activation. [94]
2B
A adenosine receptor is widely expressed in the To be activated and provide anti-tumor responses
2B
+
entire organism, although its role is not completely CD4 T-cells need the expression of the major
understood. The A receptor expression has histocompatibility complex (MHC) class II. In several
2B
been detected in type II alveolar epithelial cells, types of tumors, the loss of MHC class II is related
[73]
endothelial cells, chromaffin cells, astrocytes, to impaired levels of CD4 T-cells. Moreover, the
+
[95]
[75]
[76]
[74]
neurons, and taste cells. Moreover, A receptor levels of either MHC class II or class II transactivator
[77]
[78]
2B
is expressed also on many immune cell populations (CIITA) are altered in highly metastatic cancer cells.
[96]
including mast cells, neutrophils, dendritic cells, A receptor stimulation by repressing CIITA can
[80]
[70]
[79]
2B
macrophages, and lymphocytes. [81] impair MHC class II transcription in IFN-γ-stimulated
[74]
cells. [97,98] Moreover, bone marrow-derived dendritic
Despite A receptor binds adenosine with lower cells (BMDCs) express A receptor and adenosine
2B
2B
affinity (EC = 24 μmol/L) than A receptor, [72,82] its inhibits BMDCs IL-12p70 production via A receptor.
2A
2B
50
relevance in regulating tumor growth is becoming clear Depending on the levels of this cytokine, CD4 T-cells
+
both because its expression is highly influenced by can differentiate into Th1 or Th2 cells. The impaired
[99]
the tumor milieu and because A receptor can play production of pro-inflammatory cytokines (TNF-α and
2B
different physiological roles compared to A receptor. IL-12) and the increased IL-10 production induced by
2A
A receptor activation leads to a lower expression
2B
The tumor microenvironment is characterized by high of CD86 and MHC class II lowering CD4 T cell
+
proliferating rate of cancer cells which contribute to stimulation. [100]
hypoxia condition. Hypoxia is a very strong stimulus for
up-regulating A receptor expression through hypoxia A receptor can also affect macrophages proliferation
2B
2B
inducible factor (HIF-1α) and hypoxia-dependent induced by macrophage colony-stimulating factor
signaling pathways in endothelial cells, dendritic cells (M-CSF) [101] and the differentiation of human
(DCs), muscles, fibroblasts and T cells. [32,83-87] Indeed, monocytes, mouse peritoneal macrophages and
a functional hypoxia-responsive region within the A hematopoietic progenitor cells (HPCs) into myeloid
2B
receptor promoter has been identified, confirming DCs with tolerogenic and angiogenic features. A
[80]
2B
the selective transcriptional induction A receptor by receptor activation promotes the expansion in vitro of
2B
hypoxia. Transcription of A receptor can be induced MDSCs, that contribute to induce immunosuppression
[87]
2B
by bacterial lipopolysaccharide (LPS) or interferon by producing adenosine. [102] MDSCs potently
(IFN)-γ in macrophages, [88,89] by TNF-α in vascular suppress anti-tumor T-cell response and/or promote
smooth muscle cells, and by IL-1β in endothelial angiogenesis. [103] Altogether, these studies strongly
[90]
cells. Furthermore, a post-transcriptional regulation support a role of A receptor in inducing the
[91]
2B
of A receptor by inflammatory mediators has been differentiation of hematopoietic progenitor cells into
2B
demonstrated in endothelial and pulmonary epithelial mature cells with tolerogenic and suppressive features.
cells and in colonic epithelial cells. Therefore, Subsequent studies performed in vivo show that
[93]
[92]
although A is a low-affinity adenosine receptor, A deficient mice have reduced amounts of tumor-
2B
2B
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ July 17, 2017 131