Immunosuppressive activities of adenosine in cancer
Introduction
Suppression of anti-tumor immunity is now recognized as a hallmark of cancer and a pivotal step in tumor progression. Over the past few years, multiple immunosuppressive mechanisms implemented by tumors to evade immune-mediated destruction have been uncovered [1]. Amongst them, the engagement of co-inhibitory receptors expressed by T cells, also called immune checkpoints, has revolutionized the field and strongly renewed the interest for the development of immune-based therapies to treat cancer [2]. While immune checkpoints like PD-1 and CTLA-4 receptors have proven their clinical benefit and have led to the development of breakthrough drugs, a new wave of immune checkpoints inhibitors is currently being evaluated in preclinical and clinical studies [2, 3••]. Amongst this next-generation of immuno-oncology drugs, some targeting adenosine-mediated immunosuppression via CD73 and A2a receptor have now entered phase I clinical trials as monotherapy or in combination with PD-1/PD-L1 inhibition [4•, 5•].
With ATP, adenosine is one of the most abundant intracellular metabolites but also an important autocrine/paracrine messenger [6, 7]. Adenosine can be found in the extracellular space following active transport through the plasma membrane or following extracellular ATP degradation by the concerted action of two ecto-nucleotidases: CD39 and CD73 (see Figure 1) [7]. CD73 is considered as the rate limiting enzyme for adenosine production as it catalyzes the irreversible dephosphorylation of AMP into adenosine. In the extracellular space, adenosine can locally activate 4 subtypes of specific G protein-coupled receptors (the A1, A2a, A2b and A3 receptors) [6]. Extracellular adenosine is also rapidly recaptured by the cell or degraded into inosine thereby explaining its local signaling effects and its short half-life [7]. Upon activation, Gi-coupled A1 and A3 receptors inhibit adenylate cyclase and cyclic AMP production while Gs-coupled A2a and A2b receptors stimulate cAMP synthesis and downstream signaling pathways [6]. As a consequence, activation of A2a and A2b receptors on immune cells induces strong immunosuppressive effects through the cAMP/PKA-mediated inhibition of NF-κB, TCR and JAK–STAT signaling pathways [8]. While immunosuppressive functions of adenosine have been shown to be critical to protect tissues against excessive inflammation and to initiate tissue repair after injury [9, 10], adenosine-mediated repression of immunity has also been demonstrated to promote tumor growth and to severely impair cancer immunosurveillance [11]. Accordingly, the therapeutic blockade of adenosine signaling or adenosine generating pathways has rapidly emerged as a promising approach for cancer immunotherapy [4•, 5•, 12•, 13]. Multiple studies, conducted by our group and others, have contributed to establish CD73 and the A2a receptor as the most relevant targets to hit in the aim of preventing adenosine-mediated suppression of anti-tumor immunity [14, 15, 16, 17•, 18, 19••, 20••, 21•, 22, 23••, 24, 25, 26••, 27, 28]. Building on those compelling results, phase I clinical trials are now underway to evaluate the safety and the early efficacy of CD73 and A2a blockers in cancer patients. In light of these exciting new developments, we here give an overview of the multiple immunosuppressive activities of adenosine in the tumor microenvironment.
Section snippets
Accumulation of adenosine in the tumor microenvironment
In the tumor microenvironment (TME), ATP is abundantly released in the extracellular space due to cell death, cell stress, and activation of pannexin/connexin channels on immune cells and endothelial cells [29, 30]. Once in the extracellular medium, pro-inflammatory actions of ATP through the activation of P2X and P2Y receptors expressed by immune cells have a critical role in the initiation of anti-cancer immune responses [30, 31, 32]. However, potent signals present in the TME can favor the
Dendritic cells
ATP release from dying tumor cells represents a critical danger signal for dendritic cells favoring their maturation and the initiation of Th1 anti-tumor immune responses in a P2X7, NLRP3 and IL-1β dependent manner [31, 32]. In sharp contrast, adenosine has been shown to diminish the capacity of DCs to prime and amplify Th1 immune responses [79]. In fact, adenosine induced aberrant monocyte to DC differentiation, skewing them toward a Th2, pro-angiogenic and tolerogenic phenotype characterized
Targeting the ecto-nucleotidases
A number of studies have investigated the potential of targeting the adenosine pathway to improve anti-tumor immunity. This includes targeting CD73 with either a monoclonal antibody [15, 17•, 18, 23••, 81, 95] or a pharmacological inhibitor [14, 15, 21•, 24, 27] to enhance anti-tumor immunity. The therapeutic effect of targeting CD73 is predominantly due to inhibition of tumor-derived adenosine production and concurrent alleviation of A2a mediated immunosuppression of anti-tumor T cell
Conclusions
Adenosine-mediated immunosuppression is a critical physiological mechanism to protect tissues against excessive inflammation and promote tissue repair after injury. In the tumor microenvironment, this process is hijacked and exploited to dampen anti-tumor immunity and promote cancer progression. Since the seminal work of Sitkovsky and colleagues demonstrating the role of A2a receptor in immune homeostasis, multiple studies have highlighted the potential of targeting the adenosine pathway to
Conflict of interest statement
John Stagg is a paid consultant, scientific adviser and own stock of Surface Oncology Inc. and received research contracts from MedImmune LLC, Surface Oncology and Palobiofarma LLC. He was a paid consultant for Merck, Glaxo-Smith-Kline, MedImmune, Palobiofarma, and Sanofi.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
B Allard is supported by a MITACS Elevate fellowship. J Stagg is supported by the Famille Jean-Guy Sabourin Research Chair and by a CIHR New Investigator Award. PA Beavis was supported by a National Breast Cancer Fellowship (ID# PF-14-008) and P. K. Darcy was supported by a National Health and Medical Research Council (NHMRC) Senior Research Fellowship and project grants from the NHMRC and Cancer Council of Victoria.
References (107)
- et al.
Immune suppressive mechanisms in the tumor microenvironment
Curr Opin Immunol
(2016) - et al.
Immune checkpoint blockade: a common denominator approach to cancer therapy
Cancer Cell
(2015) Extracellular adenosine signaling in molecular medicine
J Mol Med
(2013)- et al.
CD73-deficient mice have increased antitumor immunity and are resistant to experimental metastasis
Cancer Res
(2011) - et al.
Regulation of ecto-5′-nucleotidase by TNF-α in human endothelial cells
Mol Cell Biochem
(2002) - et al.
Generation of anti-inflammatory adenosine by leukocytes is regulated by TGF-β
Eur J Immunol
(2011) - et al.
Ectonucleotidases CD39 and CD73 on OvCA cells are potent adenosine-generating enzymes responsible for adenosine receptor 2A-dependent suppression of T cell function and NK cell cytotoxicity
Cancer Immunol Immunother
(2011) - et al.
Antagonism of adenosine A2A receptor expressed by lung adenocarcinoma tumor cells and cancer associated fibroblasts inhibits their growth
Cancer Biol Ther
(2013) - et al.
Adenosinergic immunosuppression by human mesenchymal stromal cells requires co-operation with T cells
Stem Cells
(2016) - et al.
Tumor-derived exosomes regulate expression of immune function-related genes in human T cell subsets
Sci Rep
(2016)
Adenosine-mediated inhibition of the cytotoxic activity and cytokine production by activated natural killer cells
Cancer Res
Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironment
Cancer Res
An adenosine-mediated signaling pathway suppresses prenylation of the GTPase Rap1B and promotes cell scattering
Sci Signal
Combination cancer immunotherapy and new immunomodulatory targets
Nat Rev Drug Discov
CD73-adenosine: a next-generation target in immuno-oncology
Immunotherapy
Anti-CD73 in cancer immunotherapy: awakening new opportunities
Trends Cancer
Adenosine receptors as drug targets — what are the challenges?
Nat Rev Drug Discov
Suppression of inflammatory and immune responses by the A2A adenosine receptor: an introduction
Br J Pharmacol
Adenosine, an endogenous distress signal, modulates tissue damage and repair
Cell Death Differ
Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage
Nature
CD73-generated adenosine: orchestrating the tumor-stroma interplay to promote cancer growth
J Biomed Biotechnol
A2aR antagonists: next generation checkpoint blockade for cancer immunotherapy
Comput Struct Biotechnol J
Targeting cancer-derived adenosine: new therapeutic approaches
Cancer Discov
CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression
Cancer Res
Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs
Clin Cancer Res
Anti-CD39 and anti-CD73 antibodies A1 and 7G2 improve targeted therapy in ovarian cancer by blocking adenosine-dependent immune evasion
Am J Transl Res
Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis
Proc Natl Acad Sci U S A
Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor T-cell responses
Cancer Immunol Res
Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor
Cancer Res
Adenosine limits the therapeutic effectiveness of anti-CTLA4 mAb in a mouse melanoma model
Am J Cancer Res
Enhancement of tumor immunotherapy by deletion of the A2A adenosine receptor
Cancer Immunol Immunother
CD73 is associated with poor prognosis in high-grade serous ovarian cancer
Cancer Res
CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer
Proc Natl Acad Sci U S A
Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors
Proc Natl Acad Sci U S A
Immunological mechanisms of the antitumor effects of supplemental oxygenation
Sci Transl Med
CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice
J Clin Invest
A2A adenosine receptor protects tumors from antitumor T cells
Proc Natl Acad Sci U S A
Increased level of extracellular ATP at tumor sites: in vivo imaging with plasma membrane luciferase
PLoS ONE
Immunogenic cell death in cancer therapy
Annu Rev Immunol
Tumor cell death and ATP release prime dendritic cells and efficient anticancer immunity
Cancer Res
Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β-dependent adaptive immunity against tumors
Nat Med
Hostile, hypoxia-A2-adenosinergic tumor biology as the next barrier to overcome for tumor immunologists
Cancer Immunol Res
Systemic oxygenation weakens the hypoxia and hypoxia inducible factor 1α-dependent and extracellular adenosine-mediated tumor protection
J Mol Med
Transcriptional control of adenosine signaling by hypoxia-inducible transcription factors during ischemic or inflammatory disease
J Mol Med
Central role of Sp1-regulated CD39 in hypoxia/ischemia protection
Blood
Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors
J Exp Med
Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia
J Clin Invest
Adenosine A2A receptor is a unique angiogenic target of HIF-2alpha in pulmonary endothelial cells
Proc Natl Acad Sci U S A
HIF-dependent induction of adenosine A2B receptor in hypoxia
FASEB J Off Publ Fed Am Soc Exp Biol
HIF-1-dependent repression of adenosine kinase attenuates hypoxia-induced vascular leak
Blood
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