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Targeting immunosuppressive adenosine in cancer

A Corrigendum to this article was published on 01 December 2017

This article has been updated

Key Points

  • The adenosinergic pathway encompasses ectonucleotidases (CD39 and CD73) and adenosine receptors (A1R, A2AR, A2BR and A3R) that participate in the generation and signalling of adenosine in the tumour microenvironment (TME), respectively. Of the four adenosine receptors, the cyclic AMP (cAMP)-activating receptors A2AR and A2BR predominantly exert immunosuppressive functions in the TME.

  • Molecules of this pathway are regulated by several immunogenic and genetic drivers. Of these, hypoxia and transforming growth factor-β (TGFβ) represent the key drivers of the adenosinergic pathway.

  • Within a tumour niche, adenosinergic molecules are expressed by tumour cells, stromal cells and immune cells, and their critical point of action is not yet fully understood.

  • Adenosine, through activation of cAMP, can directly regulate tumour proliferation, survival, adhesion and migration. In immune cells, adenosine molecules greatly hamper vital immune effector cell functions and may be involved in mediating T cell exhaustion.

  • Novel antibodies and small molecules targeted to members of the adenosinergic pathway are now reaching clinical trials in patients with advanced cancer and may be combined with standard-of-care therapies and novel immunotherapies.

Abstract

Despite the success of anti-programmed cell death protein 1 (PD1), anti-PD1 ligand 1 (PDL1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA4) therapies in advanced cancer, a considerable proportion of patients remain unresponsive to these treatments (known as innate resistance). In addition, one-third of patients relapse after initial response (known as adaptive resistance), which suggests that multiple non-redundant immunosuppressive mechanisms coexist within the tumour microenvironment. A major immunosuppressive mechanism is the adenosinergic pathway, which now represents an attractive new therapeutic target for cancer therapy. Activation of this pathway occurs within hypoxic tumours, where extracellular adenosine exerts local suppression through tumour-intrinsic and host-mediated mechanisms. Preclinical studies in mice with adenosine receptor antagonists and antibodies have reported favourable antitumour immune responses with some definition of the mechanism of action. Currently, agents targeting the adenosinergic pathway are undergoing first-in-human clinical trials as single agents and in combination with anti-PD1 or anti-PDL1 therapies. In this Review, we describe the complex interplay of adenosine and adenosine receptors in the development of primary tumours and metastases and discuss the merits of targeting one or more components that compose the adenosinergic pathway. We also review the early clinical data relating to therapeutic agents inhibiting the adenosinergic pathway.

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Figure 1: Adenosine generation and signalling.
Figure 2: Effect of adenosinergic molecules on the tumour and surrounding stroma.
Figure 3: Adenosine-mediated immunosuppression in the tumour microenvironment.
Figure 4: Regulation of adenosinergic molecules in the tumour microenvironment.
Figure 5: Co-targeting members of the adenosinergic pathway to facilitate lymphocyte-mediated cytotoxicity.
Figure 6: Potential for targeting adenosinergic molecules to synergize with other cancer therapies.

Change history

  • 22 November 2017

    When the article was initially published online, reference 80 was incorrectly listed in the reference list. This has now been corrected in the print and online versions of the article.

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Acknowledgements

The authors wish to thank J. Jaen (Arcus Biosciences) and K. Sachsenmeier (AstraZeneca) for helpful discussions. M.J.S. was supported by a National Health and Medical Research Council of Australia (NHMRC) Senior Research Fellowship (1078671), an NHMRC Project Grant (1120887) and a Research Agreement from MedImmune. M.W.L.T. was supported by an NHMRC Project Grant (1120887).

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Contributions

D.V., M.W.L.T, and M.J.S. researched the data for the article. A.Y. provided a substantial contribution to discussions of the content. D.V. wrote the article, and all authors contributed equally to reviewing and/or editing the manuscript before submission.

Corresponding author

Correspondence to Mark J. Smyth.

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Competing interests

M.J.S. declares scientific research agreements with Bristol-Myers Squibb, Corvus Pharmaceuticals and Aduro Biotech. All other authors declare no conflict of interest.

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Glossary

Hypoxia

The disorganized arrangement of blood vessels around a tissue such as cancer, which often results in irregular distribution of oxygen within that tissue; low oxygen levels are often seen in regions of tissues further away from blood vessels.

Ectonucleotidases

Families of nucleotide-metabolizing enzymes that possess an active catalytic site and are expressed on the plasma membrane. These enzymes are associated with the catalysis of nucleotides to their corresponding nucleosides.

Regulatory T cells

(Treg cells). A subpopulation of CD4+ T cells that are involved in modulating inflammation and preventing autoimmunity. However, in the tumour microenvironment, the accumulated presence of these suppressor populations has an important role in impairing antitumour immunity.

Adoptive cellular therapies

(ACTs). Treatments used to help the immune system fight diseases, such as cancer and infections with certain viruses. T cells are collected from a patient and grown ex vivo to increase the number of T cells that are able to kill cancer cells or fight infections. These T cells are then infused back into the patient. Also called cellular adoptive immunotherapy.

Recurrence-free survival

Relating to cancer therapy, refers to the time after a treatment when patients show no signs of disease re-appearance (that is, these patients are cancer-free). This is also called disease-free survival or relapse-free survival.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of myeloid immune cells that originate from the bone marrow and exhibit potent suppressive functions.

Exosomes

Microvesicles of endocytic origin that are secreted by several cells, including tumour cells.

Mesothelioma

An aggressive form of cancer originating around the lining (mesothelium) of organs such as the lungs, abdomen or heart.

Exhausted or dysfunctional T cells

A state of T cells generally associated with progressive loss of T cell effector functions, resulting in exhaustion or dysfunction. Exhausted T cells are commonly observed during many chronic infections and cancer.

Hyperoxic conditions

A condition where cells or tissues are exposed to an elevated concentration of oxygen.

Stable disease

A term commonly used in cancer to describe the condition where tumours neither progress to distant organs nor regress.

G protein-coupled receptors

(GPCRs). Transmembrane receptors that detect extracellular molecules to initiate signalling pathways essential for cellular processes and maintenance of homeostasis.

Proliferative centres

Regions within a tumour microenvironment that are characterized by increased tumour proliferation and are commonly identified by elevated Ki-67 staining.

Scleroderma

An autoimmune condition that affects the connective tissue in the body. Scleroderma commonly results in thickening and hardening of skin in areas such as the hands and face.

Salvage pathway

A pathway in which nucleosides that have been released during RNA and DNA degradation are synthesized to form nucleotides. The activation of this pathway is usually observed in cells or tissues that are unable to undergo de novo synthesis.

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Vijayan, D., Young, A., Teng, M. et al. Targeting immunosuppressive adenosine in cancer. Nat Rev Cancer 17, 709–724 (2017). https://doi.org/10.1038/nrc.2017.86

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