Elsevier

Pharmacological Research

Volume 76, October 2013, Pages 34-40
Pharmacological Research

Review
Adenosine receptors as potential targets in melanoma

https://doi.org/10.1016/j.phrs.2013.07.002Get rights and content

Abstract

Melanoma is one of the most aggressive types of cancer, that is difficult to manage clinically. A major feature of melanoma cells is their ability to escape immune surveillance. Adenosine receptors play a pivotal role in host immune-surveillance. A2a (A2aR) and, partially, A2bR receptors mediate the adenosine-induced immune-suppression, which markedly facilitates tumor development/progression. On the contrary, A3R stimulation enhances the anti-tumor immune response and thus limits tumor growth. A3R also inhibits the proliferation of many cancer cells. Given that A2aR and A3R have profound effects on tumor growth and metastasis, they are attractive targets for novel therapeutic anti-cancer agents. Here, we review the role played by A2aR and A3R in regulating cancer pathogenesis, with a focus on melanoma, and the therapeutic potential of adenosine receptors pharmacological modulation.

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

References (98)

  • T. Blanchard et al.

    Vaccines against advanced melanoma

    Clin Dermatol

    (2013)
  • G. Haskó et al.

    Adenosine: an endogenous regulator of innate immunity

    Trends Immunol

    (2004)
  • P.E. Zarek et al.

    A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells

    Blood

    (2008)
  • S.G. Kim et al.

    p53-Independent induction of Fas and apoptosis in leukemic cells by an adenosine derivative Cl-IB-MECA

    Biochem Pharmacol

    (2002)
  • S. Merighi et al.

    Adenosine receptors as mediators of both cell proliferation and cell death of cultured human melanoma cells

    J Invest Dermatol

    (2002)
  • D. Hanahan et al.

    The hallmarks of cancer

    Cell

    (2000)
  • S. Ryzhov et al.

    Host A(2B) adenosine receptors promote carcinoma growth

    Neoplasia

    (2008)
  • P. Fishman et al.

    The A3 adenosine receptor as a new target for cancer therapy and chemoprotection

    Exp Cell Res

    (2001)
  • S. Bar-Yehuda et al.

    Resistance of muscle to tumor metastases: a role for A3 adenosine receptor agonists

    Neoplasia

    (2001)
  • S. Merighi et al.

    A3 adenosine receptor activation inhibits cell proliferation via phosphatidylinositol 3-kinase/Akt-dependent inhibition of the extracellular signal-regulated kinase 1/2 phosphorylation in A375 human melanoma cells

    J Biol Chem

    (2005)
  • R.A. Hauser et al.

    Preladenant in patients with Parkinson's disease and motor fluctuations: a phase 2, double-blind, randomised trial

    Lancet Neurol

    (2011)
  • P. Fishman et al.

    Pharmacological and therapeutic effects of A3 adenosine receptor agonists

    Drug Discov Today

    (2012)
  • I. Avni et al.

    Treatment of dry eye syndrome with orally administered CF101: data from a phase 2 clinical trial

    Ophthalmology

    (2010)
  • H. Tsao et al.

    Melanoma: from mutations to medicine

    Genes Dev

    (2012)
  • P. Van der Bruggen et al.

    A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma

    Science

    (1991)
  • P.G. Coulie et al.

    A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas

    J Exp Med

    (1994)
  • Y. Kawakami et al.

    Identification of a human melanoma antigen recognized by tumour infiltrating lymphocytes associated with in vivo tumour rejection

    Proc Natl Acad Sci U S A

    (1994)
  • R.F. Wang et al.

    Identification of TRP-2 as a human tumour antigen recognized by cytotoxic T lymphocytes

    J Exp Med

    (1996)
  • Y.T. Chen et al.

    A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening

    Proc Natl Acad Sci U S A

    (1997)
  • C. Castelli et al.

    T-cell recognition of melanoma-associated antigens

    J Cell Physiol

    (2000)
  • Y. Godet et al.

    MELOE-1 is a new antigen overexpressed in melanomas and involved in adoptive T cell transfer efficiency

    J Exp Med

    (2008)
  • G.M. Halliday et al.

    Spontaneous regression of human melanoma/nonmelanoma skin cancer: association with infiltrating CD4+ T cells

    World J Surg

    (1995)
  • M.A. Lowes et al.

    Regression of melanoma, but not keratoacanthoma, is associated with increased HLA-B22 and decreased HLA-B27 and HLA-DR1

    Melanoma Res

    (1999)
  • L.V. Kalialis et al.

    Spontaneous regression of metastases from melanoma: review of the literature

    Melanoma Res

    (2009)
  • M.B. Atkins et al.

    High dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993

    J Clin Oncol

    (1999)
  • J. Dutcher

    Current status of interleukin-2 therapy for metastatic renal cell carcinoma and metastatic melanoma

    Oncology (Williston Park)

    (2002)
  • M.E. Dudley et al.

    Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens

    J Clin Oncol

    (2008)
  • M.E. Dudley et al.

    CD8+ enriched “young” tumor infiltrating lymphocytes can mediate regression of metastatic melanoma

    Clin Cancer Res

    (2010)
  • M.J. Besser et al.

    Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients

    Clin Cancer Res

    (2010)
  • S.A. Rosenberg et al.

    Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy

    Clin Cancer Res

    (2011)
  • S.A. Rosenberg

    Cell transfer immunotherapy for metastatic solid cancer – what clinicians need to know

    Nat Rev Clin Oncol

    (2011)
  • F. Pandolfi et al.

    Strategies to overcome obstacles to successful immunotherapy of melanoma

    Int J Immunopathol Pharmacol

    (2008)
  • J. Dissemond et al.

    Downregulation of tapasin expression in progressive human malignant melanoma

    Arch Dermatol Res

    (2003)
  • Y. Ben-Neriah et al.

    Inflammation meets cancer, with NF-kB as the matchmaker

    Nat Immunol

    (2011)
  • W. Zou

    Immunosuppressive networks in the tumour environment and their therapeutic relevance

    Nat Rev Cancer

    (2005)
  • D.I. Gabrilovich et al.

    Myeloid-derived suppressor cells as regulators of the immune system

    Nat Rev Immunol

    (2009)
  • D. Zikich et al.

    Immunotherapy for the management of advanced melanoma: the next steps

    Am J Clin Dermatol

    (2013)
  • M.I. Raaijmakers et al.

    Melanoma immunotherapy: historical precedents, recent successes and future prospects

    Immunotherapy

    (2013)
  • Wolchok J

    How recent advances in immunotherapy are changing the standard of care for patients with metastatic melanoma

    Ann Oncol

    (2012)
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