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

of A receptor deficient mice completely rejected response against cancer induced by inhibitors of
2A
established immunogenic tumors in a CD8 T-cell- immune checkpoints. More recently, it has been
+
[54]
dependent manner. However, 40% of tumor-bearing demonstrated that blockade of A adenosine receptor
2B
A receptor deficient mice did not reject the tumor, subtype with a selective antagonist improves survival
2A
possibly because of the expression of A receptor on and the anti-metastatic effects of anti-PD1 and anti-
2B
A receptor deficient CD8 T cells. [10] CTLA4 monoclonal antibodies in both melanoma and
+
2A
mammary cancer models of metastasis with cells
At the same time a large number of evidence show expressing CD73. The anti-metastatic effects of
[57]
that inhibition of CD73 activity or CD73 knockdown these combinations relies on the capacity of immune
on tumor cells inhibit tumor growth and metastasis by checkpoints inhibitors to boost immune responses and
enhancing the anti-tumor T cell response. [42-46] CD73- on direct effects of A adenosine receptor inhibitor
2B
deficient mice are resistant to tumor and show an on cancer cell metastasis. Here the authors show
[57]
increased influx of CD8 T cells and low number of that blockade of A receptor in A receptor deficient
[44]
+
2B
2B
Tregs within the tumor. [47] mice is able to reduce the metastasis of human triple
negative breast cancer (TNBC) xenografts, confirming
The expression of CD73 on various tumor the critical role of A receptor on cancer cells rather
2B
cells from cancer patients, including breast, [46] than host cells. Altogether these preclinical studies
[57]
glioblastoma, [48] prostate, [49] ovarian, [50] leukemia [51] strongly support the therapeutic potential of targeting
has been associated with poor prognosis. Notably, adenosine in cancer.
some chemotherapeutics are able to increase the
expression of CD73 on cancer cells, which may in Experimental evidence suggests that also CD39
turn represent a putative mechanism of resistance can represent a potential therapeutic target for
to chemotherapeutics. [46,49,51] On the other hand, cancer treatment. CD39 is highly expressed by Treg
targeting CD73 can improve the therapeutic potential cells and together with CD73 generate adenosine
of some conventional cancer treatments, including in the tumor microenvironment. Elevated levels
[58]
chemotherapy, radiotherapy and immunotherapy. of CD39-expressing Treg cells have been found in
For example, inhibition of CD73 in combination some mouse tumor tissues, including melanoma and
with doxorubicin prolonged the survival of mice with colorectal cancer. Inhibition of CD39 reduces the
[58]
metastatic breast cancer. [46] Adenosine can also impair tumor growth, enhances the recruitment of T cells in
the anti-tumor response induced by high dose of the tumor lesions and improves the effector functions
radiation therapy. [52] Administration of CD73 inhibitor of CD8 T cells and NK cells, by impairing the activity
+
into mice with tumors exposed to radiation therapy of CD39-expressing Treg cells. Although additional
[58]
can significantly reduce tumor growth. [52] Notably, studies are needed to better clarify the therapeutic
inhibition of CD73 may also improve the synergy of potential of targeting CD39 in cancer, the use of
radiation therapy in combination with anti-CTLA4 CD39 inhibitors might be useful to limit the immune
monoclonal antibody. [52] suppression induced by Treg cells.
Recent studies indicate that inhibition of adenosine/ Selective agonists of A adenosine receptor subtype
3
A adenosine receptors axis synergizes with other have proved to directly inhibit proliferation of A -
2
3
immune checkpoints inhibitors reducing potently expressing tumor cells by arresting cell cycle
tumor growth in murine models of cancer. In particular, progression and exert immunostimulatory effects
treatment of mice with monoclonal antibody anti- in some murine tumor models in a NK- and T-cell-
CD73 enhances the anti-tumor effects of antibodies dependent manner, enhancing the production of Th1-
anti-PD1 and anti-CTLA4. In support, other studies like cytokines in the tumor microenvironment. [59-63]
[53]
have demonstrated that selective blockade of A 2A A adenosine receptor agonists have been tested
3
adenosine receptor in combination with anti PD-1 indeed in some clinical trials for rheumatoid arthritis
antibody and anti-CTLA4 antibody potently reduced (NCT00280917, NCT00556894, NCT01034306,
tumor growth. [54-56] The therapeutic synergy of these NCT02647762), [64] hepatocellular carcinoma
combinations depends on the CD73 expression on (NCTNCT00790218, NCT02128958) and hepatitis
tumor cells, proving that CD73-generating adenosine (NCT00790673), dry eye syndrome (NCT01235234,
[65]
by tumor cells within the tumor microenvironment may NCT00349466) and psoriasis (NCT01265667). [67]
[66]
affect the activity of immunotherapy. Furthermore,
blockade of PD-1 enhances the expression of A Nonetheless, emerging evidence suggest that
2A
receptors on tumor-infiltrating CD8 T cells, suggesting A receptor can mediate the pro-tumor effects of
+
2B
that adenosine via A receptor limits the immune adenosine. It is known that A receptor is important
2B
2A
130 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ July 17, 2017