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

treatment currently used for several tumors, through cells. The first class of immunotherapeutics approved
[8]
which cancer cells are either directly killed upon DNA by US Food and Drug Administration (FDA) for
damage by depositing high physical energy of radiation, patients with metastatic melanoma includes antibodies
or indirectly due to the release of free radicals. against CTLA4 (Ipilimumab and Tremelimumab).
[4]
[9]
Nowadays the most novel anti-cancer strategies are Later on other immune checkpoint molecules have
the targeted-therapy and immunotherapy. The cancer been discovered, such as antibodies against PD-1
targeted-therapy uses small molecules that can block (Nivolumab, Pembrolizumab and Atezolizumab),
fundamental pathways or mutant proteins essential for PD-L1, lymphocyte-activation gene 3 (LAG3, also
tumor growth. Conversely, cancer immunotherapy is known as CD223), B7-H3 (also known as CD276),
[5]
a therapeutic strategy that improves the host immune B7-H4 (also known as B7-S1, B7x and VCTN1) and
response against cancer cells, instead of acting directly T-cell immunoglobulin domain and mucin domain 3
on tumor cells. [6] (TIM3). The therapeutic outcomes in cancer patients
[8]
is improved by combining immunotherapeutics with
Several chromosomal alterations, genetic mutations chemotherapy. The concomitant blockade of different
[8]
and genomic instability that occur in cancer cells immune checkpoints may increase the success of
provide a different set of antigens that the immune immunotherapy in cancer patients. Hence, in the
[8]
system can use to distinguish transformed cells from last few years many efforts have been made aiming
their own cells. However, tumor cells escape from host to investigate novel therapeutic strategies to inhibit
[7]
immune surveillance through different mechanisms, cancer-induced immune-suppression. It has become
that include loss of immunogenicity and ineffective clear that in the tumor microenvironment there are
T-cell mediated responses. Moreover, several several pathways that may play an important role in
inflammatory mediators including chemokines [CC- the tumor immune evasion process. Among them,
chemokine ligand 2 (CCL2), CCL5, CXC-chemokine extracellular adenosine, an ATP-derived molecule
ligand 1 (CXCL1), CXCL2, CXCL3, CXCL5, CXCL6, generated by the extracellular CD39/CD73 enzymes,
CXCL7, CXCL8, CXCL10 and CXCL12], cytokines has been identified as an immune checkpoint that
[tumor necrosis factor (TNF), interleukin 1 (IL-1), IL- critically impairs the anti-tumor immune response
4, IL-5, IL-6, IL-10 and IL-13] and growth factors mainly via A adenosine receptor subtype. [10-12]
2A
[granulocyte macrophage-colony stimulating factor Accordingly, selective inhibitors of adenosine signaling
(GM-CSF), vascular endothelial growth factor (VEGF), pathways have been tested in pre-clinical studies [13,14]
transforming growth factor-ß (TGF-ß)] are released by and some of them, including the antibody anti-CD73
tumor cells and/or stroma and immune cells surrounding and the A receptor antagonists are currently in Phase
2A
tumor tissue, generating a chronic inflammatory I clinical trials in cancer patients, either as single
microenvironment. Chronic inflammation in cancer can agents, or in combination with immune checkpoints
facilitate tumor proliferation and invasion and drive the inhibitors such as anti PD-1 monoclonal antibodies
recruitment and activation of immunosuppressive cells, [NCT02503774 and NCT02655822].
including T regulatory (Treg) cells, myeloid-derived
suppressor cells (MDSCs) and tumor-associated While the role in tumor immunity of CD73-A receptor
2A
macrophages (TAM). In this context, many inhibitory axis has been extensively examined, less is known
receptors, known as “immune checkpoint molecules” about the role of A receptor subtype in tumor
2B
such as cytotoxic T-lymphocyte-associated antigen development and progression. Compelling evidence
4 (CTLA4) and programmed cell death-1 (PD-1), are suggest that this receptor contributes to the pro-tumor
upregulated on activated lymphocytes during an active effects of adenosine within tumor microenvironment. In
immune response providing a negative feedback this article, we review the current data on the effects
mechanism. CTLA4 binds to members of the B7 of adenosine in tumor progression, focusing on the
[7]
family on antigen-presenting cells (APCs) inhibiting emerging role of A receptor in regulating tumor growth
2B
T-cell activation, while PD-1 interacts with ligands and discuss the therapeutic potential of targeting A
2B
PD-L1, expressed on different cell types including receptors in cancer treatment.
tumor cells, or PD-L2 on macrophages and dendritic
cells, inhibiting T-cell functions. [7,8] The development CRITICAL ROLES OF ADENOSINE IN
of agonist antibodies (for costimulatory pathways) or TUMOR PROGRESSION
antagonist antibodies (for inhibitory pathways) which
target lymphocyte receptors or their ligands is one Adenosine is a key endogenous molecule produced
of the most promising approach with the potential to at the extracellular level by two ectoenzymes, ecto-5’-
modulate the tumor microenvironment and improve nucleotidase (CD73) and ectonucleoside triphosphate
the efficacy of immune response/s against cancer diphosphohydrolase-1 (CD39) physiologically
128 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ July 17, 2017