Immunosuppressive activities of adenosine in cancer

https://doi.org/10.1016/j.coph.2016.04.001Get rights and content

Highlights

  • Adenosine protects tissues against excessive inflammation and promotes tissue repair.

  • The adenosine pathway is hijacked to dampen anti-tumor immunity.

  • Targeting CD73 or A2a receptor enhances anti-tumor immunity.

  • Targeting CD73 or A2a receptor synergizes with immune checkpoint inhibitors.

  • Drugs targeting CD73 or A2a are currently in phase I clinical trials.

Multiple immunosuppressive mechanisms impede anti-tumor immunity. Among them, the accumulation of extracellular adenosine is a potent and widespread strategy exploited by tumors to escape immunosurveillance through the activation of purinergic receptors. In the immune system, engagement of A2a and A2b adenosine receptors is a critical regulatory mechanism that protects tissues against excessive immune reactions. In tumors, this pathway is hijacked and hinders anti-tumor immunity, promoting cancer progression. Different groups have highlighted the therapeutic potential of blocking CD73-dependent adenosine-mediated immunosuppression to reinstate anti-tumor immunity. Phase clinical trials evaluating anti-CD73 antibodies and A2a receptor antagonists in cancer patients are currently ongoing. We here review the recent literature on the immunosuppressive effects of extracellular adenosine and discuss the development of adenosine inhibitors.

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.

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