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

expressed on both hematopoietic and non- adenosine kinase, which inhibits the metabolism of
hematopoietic cell types. [15,16] Once released in the adenosine, is down-regulated. At the same time, the
[11]
extracellular space, adenosine elicits its physiological expression of adenosine receptors A and A is also
2A
2B
responses by coupling and activating four membrane up-regulated. Consequently, adenosine along with
[32]
adenosine receptors (A , A , A , A ) which contain other HIF-induced immunosuppressive factors and
2A
1
2B
3
seven transmembrane domains coupled to G cells, contributes to modulate the functions of tumor
proteins. Once bounded with its receptors, adenosine cells, tumor-infiltrating immune cells and/or other
[17]
can inhibit (via A and A ) or stimulate (via A and A ) stroma cells.
2B
3
1
2A
the adenylyl cyclase resulting in a decrease or increase
in cyclic AMP (cAMP) accumulation, respectively. Within the hematopoietic compartment, CD39 is
[18]
+
cAMP activates the protein kinase A (PKA) and in expressed on B cells and monocytes, subsets of CD8 T
+
turn the nuclear substrate cAMP responsive element- cells, CD4 T cells and NK cells. [15,33] CD73 is expressed
binding protein (CREB) that regulates the expression on B cells and subsets of CD8 T cells, CD4 T cells and
+
+
of several genes by binding to cAMP responsive NK cells and small subsets of monocytes. [15,33] CD39
elements and other cAMP effectors such as Epac, and CD73 are co-expressed on B cells, Treg cells,
altering pro-inflammatory genes expression. [19-22] A Th17 cells, NK cells, neutrophils, tissue macrophages
2B
receptor can also activate the phospholipase C (PLC) and myeloid-derived suppressor cells (MDSCs). [15,33]
by coupling Gq protein. [23,24] All adenosine receptors CD39 and CD73 are also expressed on endothelial
are involved in the modulation of mitogen-activated cells and on the surface of several types of cancer
protein kinase (MAPK) activity. [25] cells. [14,15] Thus, CD73-expressing cells, including
immune cells and/or stroma cells, produce adenosine
The tumor milieu is characterized by high levels that accumulate in the tumor microenvironment and
of adenosine triphosphate (ATP) due to the high profoundly impairs anti-tumor immune responses.
proliferating rate of cancer cells. The ATP is rapidly Accordingly, a large number of evidence have
converted at the extracellular level in ADP and AMP proved that targeting adenosine-generating enzymes
through two reversible steps via CD39, while the significantly reduces tumor growth by improving anti-
last irreversible step in adenosine is mediated by tumor immune responses.
CD73. Under homeostatic conditions adenosine
[16]
level is low but during pathophysiological events A receptor is the most thoroughly characterized
2A
(including stress, infection, inflammation and cancer) receptor involved in the adenosine-induced anti-
extracellular adenosine levels can be increased from inflammatory/immune-suppressive effects within
10-200 nmol/L up to 10-100 μmol/L. In inflammatory- the tumor microenvironment. A receptor is highly
[26]
2A
associated conditions, adenosine typically attenuates expressed on lymphocytes, macrophages, dendritic
the inflammatory response. [26,27] Importantly, studies cells, NK cells, and neutrophils. Activation of A
2A
by Ohta and Sitkovsky showed for the first time receptor significantly reduces T-cell receptor (TCR)-
[28]
that A receptor-deficient mice are unable to control triggered effector functions, including proliferation
2A
inflammation, resulting in exaggerated immune and production of cytokines and chemokines,
responses which can trigger extensive tissue disruption preventing T cells activation and function via cAMP/
with subsequent cell death. These effects of adenosine protein kinase cAMP-dependent (PKA) pathways. [34-36]
are dependent on the activation of the adenosine A These effects occurs upon A adenosine receptor
2A
2A
receptors on immune cells, which induce a wide range stimulation in naïve CD4 T cells as well as in CD8
+
+
of singular immunosuppressive responses which T cells. Furthermore, A receptor stimulation reduces
2A
regulate the uncontrolled inflammation to harmful the expression of CD25 and CD40 ligand (CD40L)
insults. [27,29,30] However, in the context of tumor while and increases the expression of PD-1 and CTLA-
extracellular ATP increases the T-cell mediated effector 4 on T cells, inducing T cell anergy that promotes
[37]
function, high levels of adenosine mediates opposite peripheral tolerance. Stimulation of A receptor on
[35]
2A
effects favoring immune suppression that is associated myeloid cells can also affect the release of IL-12 and
with tumor growth and metastasis. Hypoxia, which is induce the production of IL-10, affecting significantly
[31]
[38]
a common feature of the tumor microenvironment that the T- and NK-cell responses in the solid tumor
promotes immunosuppression, is one of the main factors microenvironment. Additional evidence also show
[39]
responsible of the increased production of adenosine that A adenosine receptor stimulation promotes the
2A
within many solid tumors. Indeed, the expression development of immune suppressive myeloid cells
[40]
[11]
and the enzymatic activities of CD39 and CD73, or Treg cells. The first in vivo genetic evidence of
[41]
responsible of the adenosine generation, increased the role of A receptor in tumor progression has
2A
under hypoxic conditions, while the expression of the been reported by Ohta et al. who showed that 60%
[10]
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ July 17, 2017 129