ReviewAdenosine receptors as potential targets in melanoma
Graphical abstract
Introduction
Melanoma is a potentially lethal tumor, that arises from melanocytes present in the skin, mucosa or epithelial surfaces of the eyes and ears [1]. Melanoma cells have the potential to spread, and metastatic melanoma is highly resistant to conventional chemotherapy. Currently, dacarbazine is the chemotherapeutic drug of choice used for treating metastatic melanoma, despite the low response rate contributing only 8 months median survival [2]. Recently, it has been demonstrated that some cytotoxic agents, including dacarbazine, have also immune-stimulatory effects [3]. It is well known that melanoma is one of the most immunogenic types of cancer. Melanoma cells express a variety of melanoma-associated antigens (MAAs), which are recognized by T lymphocytes. These antigens belong to three main groups: tumor-associated testis-specific antigens (MAGE, BAGE, GAGE and PRAME), melanocyte differentiation antigens (tyrosinase, Melan-A/MART-1, gp100, TRP-1 and TRP-2) and mutated or aberrantly expressed antigens (MUM-1, CDK4, β-catenin, gp100-in4, p15 and N-acetylglucosaminyltransferase V) [4], [5], [6], [7], [8], [9], [10]. In a few cases, patients with established melanoma can have spontaneous tumor regression, suggesting that the induction of a specific anti-tumor immune response, which is mediated by T cells, can indeed be achieved [11], [12], [13].
Some clinical protocols directed to maintain pre-existing or adoptively transferred melanoma-specific T cells are currently used. Interleukin (IL)-2 treatment, which has an unbiased response rate of 15–20%, has been approved by the Food and Drug Administration (FDA) [14], [15]. Further, the adoptive transfer of autologous tumor-infiltrating lymphocytes (TILs) is a promising anti-tumor therapy in patients with melanoma [16], [17], [18]. TIL therapy has shown a clinical response in 49–72% of patients with metastatic melanoma and a long lasting complete response rate of 40% [19], [20], [21]. However, numerous strategies to treat melanoma with immunotherapy have been only partially successful [22]. Various mechanisms have been implicated in the escaping of an anti-tumor immune response in vivo. Melanoma cells evade T-cell-immune-mediated destruction by down-regulating the expression of class I Human Leukocyte Antigen (HLA) of the MAAs and the production of multiple immunosuppressive factors that cause the generation of a chronic inflammatory microenvironment [23], [24], [25]. During chronic inflammation, several inflammatory factors are released including cytokines, chemokines, growth factors, reactive oxygen and nitrogen species as well as prostaglandins from the surrounding tissue and/or tumor cells [26], [27], [28]. Inflammatory factors, which were present in the melanoma microenvironment, consist of chemokines (CC-chemokine ligand 2, CCL2; CCL5; CXC-chemokine ligand 1, CXCL1; CXCL2; CXCL3; CXCL5; CXCL6; CXCL7; CXCL8; CXCL10 and CXCL12), as well as growth factors (granulocyte macrophage-colony stimulating factor, GM-CSF; vascular endothelial growth factor, VEGF; transforming growth factor-β, TGF-β) and cytokines (tumor necrosis factor, TNF, IL-1, IL-4, IL-5, IL-6, IL-10 and IL-13) [25], [29]. These factors, produced by tumor, stroma and immune cells, promote melanoma growth and progression. They can drive the recruitment and activation of many immunosuppressive cells in the tumor environment, including T regulatory cells (Tregs) [30] myeloid-derived suppressor cells (MDSCs) [31] and tumor-associated macrophages (TAMs) [32]. Both inflammatory factors and immunosuppressive cells play a critical role in limiting the effectiveness of anti-tumor immunotherapy [29], [30].
The first successful attempt to abolish immune-suppression in melanoma treatment has been achieved with the use of the recently FDA-approved monoclonal antibody (mAb) ipilimumab. Ipilimumab binds to the cytotoxic T lymphocyte antigen-4 (CTLA-4) [33], [34], [35], [36], which is expressed on activated CD4+ T cells and CD8+ T cells. Its interaction with members of the B7 family on antigen-presenting cells (APCs) inhibits T-cell activation. Ipilimumab competes successfully for B7 binding with the co-stimulatory receptor CD28. Ipilimumab therapy improves the overall survival rate in patients with metastatic melanoma determining a 32% reduction in the risk of death compared to the control group [37].
Taken together, these findings emphasize the great potential of immune-active therapies against melanoma and the importance of investigating novel therapeutic strategies aimed at the inhibition of cancer-induced immune-suppression, that in turn may restore an efficient anti-tumor immune response.
Section snippets
Adenosine: a critical modulator of immune response in the tumor environment
Numerous evidences suggest that adenosine plays a pivotal role in endogenous immunosuppressive pathways which regulate immune responses in the tumor microenvironment [38], [39]. Adenosine is an adenosine triphosphate (ATP)-derived molecule, whose effects are mediated by four different membrane-spanning G-protein-coupled receptors (GPCRs): A1R, A2aR, A2bR and A3R [40] (Fig. 1). A2a and A2b are Gs-coupled receptors, that by increasing intracellular cyclic AMP (cAMP) levels (Fig. 1), mediate the
A2a receptors
A2aR is expressed in the brain, in blood vessels, on blood platelets, in the olfactory bulb, on immune cells, including neutrophils, monocytes, macrophages, dendritic cells (DCs), T cells and NK cells [40], [47], [71]. It is also expressed, at lower levels, in the heart, lung and blood vessels [40], [71]. A2aR, among all four adenosine receptors, has the highest affinity for adenosine and its activation has been linked to Gs-mediated activation of AC, which increases the levels of cAMP (Table 1
A2aR antagonism
A2aR expression in human melanoma cell lines was originally reported by Merighi et al. [80]. These authors demonstrated that adenosine enhances melanoma cell proliferation through A2aR activation. However, they also reported that A2aR triggers to melanoma cell death, which is counterbalanced by A3R stimulation [81]. Thus, the A2aR-induced signaling pathway in human A375 melanoma cells promotes both proliferation and cell death, probably as a consequence of the different expression pattern of
Conclusions
It is clear that adenosine modulates significantly tumor growth and metastasis through its receptors, implying a therapeutic potential of some adenosine receptor-targeted molecules as anti-cancer agents. Although more research is needed on ARs function in melanoma, it is evident that both A2aR and A3R may affect profoundly melanoma growth. Block of A2aR hampers the adenosine-induced immune suppression in tumor, restoring an efficient T cell response. Selective A2aR antagonists could be used to
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2020, Current Opinion in PharmacologyCitation Excerpt :As such, it represents an attractive therapeutic candidate for modulating immune function, with extremely promising preclinical data in the context of tumor immunotherapy. To this end, the adenosine-A2AR pathway has been extensively reviewed with emphasis on its potential as a therapeutic target for cancer [3–12]. However, the early clinical experience has not yet generated results as dramatic as those observed in mice.
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2017, Comparative Biochemistry and Physiology Part - C: Toxicology and PharmacologyCitation Excerpt :This purine nucleoside promotes its effects by binding and activating four P1 adenosine receptors: A1, A2A, A2B and A3, which are G-protein-coupled cell-surface receptors (Haskó et al., 2008; Ferrari et al., 2016). Adenosine binding to A1 and A3 receptor subtypes leads to an inhibition of adenylate cyclase enzyme, decreasing cyclic AMP levels, whereas the activation of A2A and A2B subtypes causes the stimulation of adenylate cyclase, resulting in increased cyclic AMP levels (Burnstock, 2007; Montinaro et al., 2013). During inflammation, excessive damage to healthy tissues can compromise the normal functions and it must be controlled by resolution mechanisms, and adenosine is involved in these processes through their anti-inflammatory effects.