Abstract
Cancer immunotherapy based on immune-checkpoint inhibition or adoptive cell therapy has revolutionized cancer care. Nevertheless, a large proportion of patients do not benefit from such treatments. Over the past decade, remarkable progress has been made in the development of ‘next-generation’ therapeutics in immuno-oncology, with inhibitors of extracellular adenosine (eADO) signalling constituting an expanding class of agents. Induced by tissue hypoxia, inflammation, tissue repair and specific oncogenic pathways, the adenosinergic axis is a broadly immunosuppressive pathway that regulates both innate and adaptive immune responses. Inhibition of eADO-generating enzymes and/or eADO receptors can promote antitumour immunity through multiple mechanisms, including enhancement of T cell and natural killer cell function, suppression of the pro-tumourigenic effects of myeloid cells and other immunoregulatory cells, and promotion of antigen presentation. With several clinical trials currently evaluating inhibitors of the eADO pathway in patients with cancer, we herein review the pathophysiological function of eADO with a focus on effects on antitumour immunity. We also discuss the treatment opportunities, potential limitations and biomarker-based strategies related to adenosine-targeted therapy in oncology.
Key points
-
Abundant evidence indicates that the conversion of pro-inflammatory extracellular ATP into immunosuppressive extracellular adenosine (eADO) favours tumour progression and escape from antitumour immunity.
-
The production of eADO primarily involves the concerted action of the cell-surface ectonucleotidases CD39 and CD73; however, alternative pathways involve the enzymatic activity of tissue-non-specific alkaline phosphatases and the NAD+ ectohydrolase CD38 as well as cellular export of cytosolic adenosine.
-
Activation of adenosine receptors A2A and A2B on tumour-infiltrating immune cells suppresses the antitumour activities of these cells; A2B signalling in tumour cells themselves further promotes their survival and metastasis.
-
In preclinical models, targeted inhibition of CD73, CD39, CD38, A2A or A2B can restore antitumour immunity and enhance the efficacy of cancer immunotherapies.
-
Clinical trials investigating the antitumour activity of eADO pathway inhibitors in patients with cancer are underway and preliminary evidence of therapeutic efficacy has been reported.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Change history
15 February 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41571-020-0415-x
References
Wolberg, G., Zimmerman, T. P., Hiemstra, K., Winston, M. & Chu, L. C. Adenosine inhibition of lymphocyte-mediated cytolysis: possible role of cyclic adenosine monophosphate. Science 187, 957–959 (1975).
Henney, C. S., Bourne, H. R. & Lichtenstein, L. M. The role of cyclic 3′,5′ adenosine monophosphate in the specific cytolytic activity of lymphocytes. J. Immunol. 108, 1526–1534 (1972).
Strom, T. B., Deisseroth, A., Morganroth, J., Carpenter, C. B. & Merrill, J. P. Alteration of the cytotoxic action of sensitized lymphocytes by cholinergic agents and activators of adenylate cyclase. Proc. Natl Acad. Sci. USA 69, 2995–2999 (1972).
Blay, J., White, T. D. & Hoskin, D. W. The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res. 57, 2602–2605 (1997).
Ohta, A. & Sitkovsky, M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414, 916–920 (2001).
Ohta, A. et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc. Natl Acad. Sci. USA 103, 13132–13137 (2006).
Sun, X. et al. CD39/ENTPD1 expression by CD4+ Foxp3+ regulatory T cells promotes hepatic metastatic tumor growth in mice. Gastroenterology 139, 1030–1040 (2010).
Stagg, J. et al. Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc. Natl Acad. Sci. USA 107, 1547–1552 (2010).
Stagg, J. et al. CD73-deficient mice have increased antitumor immunity and are resistant to experimental metastasis. Cancer Res. 71, 2892–2900 (2011).
Stagg, J. et al. CD73-deficient mice are resistant to carcinogenesis. Cancer Res. 72, 2190–2196 (2012).
Wang, L. et al. CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. J. Clin. Invest. 121, 2371–2382 (2011).
Yegutkin, G. G. et al. Altered purinergic signaling in CD73-deficient mice inhibits tumor progression. Eur. J. Immunol. 41, 1231–1241 (2011).
Jin, D. et al. CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression. Cancer Res. 70, 2245–2255 (2010).
Kaczmarek, E. et al. Identification and characterization of CD39/vascular ATP diphosphohydrolase. J. Biol. Chem. 271, 33116–33122 (1996).
Ferrari, D., Chiozzi, P., Falzoni, S., Hanau, S. & Di Virgilio, F. Purinergic modulation of interleukin-1 beta release from microglial cells stimulated with bacterial endotoxin. J. Exp. Med. 185, 579–582 (1997).
Boison, D. & Yegutkin, G. G. Adenosine metabolism: emerging concepts for cancer therapy. Cancer Cell 36, 582–596 (2019).
Boison, D. in The Adenosine Receptors 13–32 (Humana Press, 2018).
Ferretti, E., Horenstein, A. L., Canzonetta, C., Costa, F. & Morandi, F. Canonical and non-canonical adenosinergic pathways. Immunol. Lett. 205, 25–30 (2019).
Yegutkin, G. G., Henttinen, T., Samburski, S. S., Spychala, J. & Jalkanen, S. The evidence for two opposite, ATP-generating and ATP-consuming, extracellular pathways on endothelial and lymphoid cells. Biochemical J. 367, 121–128 (2002).
Zimmermann, H. 5’-Nucleotidase: molecular structure and functional aspects. Biochem. J. 285, 345–365 (1992).
Donaldson, S. H., Picher, M. & Boucher, R. C. Secreted and cell-associated adenylate kinase and nucleoside diphosphokinase contribute to extracellular nucleotide metabolism on human airway surfaces. Am. J. Respir. Cell Mol. Biol. 26, 209–215 (2002).
Deterre, P. et al. Coordinated regulation in human T cells of nucleotide-hydrolyzing ecto-enzymatic activities, including CD38 and PC-1. Possible role in the recycling of nicotinamide adenine dinucleotide metabolites. J. Immunol. 157, 1381–1388 (1996).
Horenstein, A. L. et al. A CD38/CD203a/CD73 ectoenzymatic pathway independent of CD39 drives a novel adenosinergic loop in human T lymphocytes. Oncoimmunology 2, e26246 (2013).
Street, S. E. et al. Tissue-nonspecific alkaline phosphatase acts redundantly with PAP and NT5E to generate adenosine in the dorsal spinal cord. J. Neurosci. 33, 11314–11322 (2013).
Moser, G. H., Schrader, J. & Deussen, A. Turnover of adenosine in plasma of human and dog blood. Am. J. Physiol. 256, C799–C806 (1989).
Latini, S. & Pedata, F. Adenosine in the central nervous system: release mechanisms and extracellular concentrations. J. Neurochem. 79, 463–484 (2001).
Williams-Karnesky, R. L. et al. Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis. J. Clin. Invest. 123, 3552–3563 (2013).
Morote-Garcia, J. C., Rosenberger, P., Kuhlicke, J. & Eltzschig, H. K. HIF-1–dependent repression of adenosine kinase attenuates hypoxia-induced vascular leak. Blood 111, 5571–5580 (2008).
Decking, U. K. M., Schlieper, G., Kroll, K. & Schrader, J. Hypoxia-induced inhibition of adenosine kinase potentiates cardiac adenosine release. Circ. Res. 81, 154–164 (1997).
Morote-Garcia, J. C., Rosenberger, P., Nivillac, N. M. I., Coe, I. R. & Eltzschig, H. K. Hypoxia-inducible factor-dependent repression of equilibrative nucleoside transporter 2 attenuates mucosal inflammation during intestinal hypoxia. Gastroenterology 136, 607–618 (2009).
Song, A. et al. Erythrocytes retain hypoxic adenosine response for faster acclimatization upon re-ascent. Nat. Commun 8, 14108 (2017).
Liu, H. et al. Beneficial role of erythrocyte adenosine A2B receptor-mediated AMP-activated protein kinase activation in high-altitude hypoxia. Circulation 134, 405–421 (2016).
Eltzschig, H. K. et al. HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia. J. Exp. Med. 202, 1493–1505 (2005).
Müller, C. E. & Jacobson, K. A. Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim. Biophys. Acta 1808, 1290–1308 (2011).
Fredholm, B. B. Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ. 14, 1315–1323 (2007).
Fredholm, B. B., IJzerman, A. P., Jacobson, K. A., Linden, J. & Müller, C. E. International union of basic and clinical pharmacology. LXXXI. nomenclature and classification of adenosine receptors — an update. Pharmacol. Rev. 63, 1–34 (2011).
Merighi, S., Gessi, S. & Borea, P. A. in The Adenosine Receptors 33–57 (Humana Press, 2018).
Haskó, G. et al. Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock. J. Immunol. 164, 1013–1019 (2000).
He, B. et al. Resetting microbiota by Lactobacillus reuteri inhibits T reg deficiency–induced autoimmunity via adenosine A2A receptors. J. Exp. Med. 214, 107–123 (2017).
Welihinda, A. A., Kaur, M., Greene, K., Zhai, Y. & Amento, E. P. The adenosine metabolite inosine is a functional agonist of the adenosine A2A receptor with a unique signaling bias. Cell. Signal. 28, 552–560 (2016).
Di Virgilio, F., Sarti, A. C., Falzoni, S., De Marchi, E. & Adinolfi, E. Extracellular ATP and P2 purinergic signalling in the tumour microenvironment. Nat. Rev. Cancer 18, 601–618 (2018).
Cekic, C. & Linden, J. Purinergic regulation of the immune system. Nat. Rev. Immunol. 16, 177–192 (2016).
Chen, Y. et al. ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314, 1792–1795 (2006).
Aymeric, L. et al. Tumor cell death and ATP release prime dendritic cells and efficient anticancer immunity. Cancer Res. 70, 855–858 (2010).
Antonioli, L., Fornai, M., Blandizzi, C. & Haskó, G. in The Adenosine Receptors 499–514 (Humana Press, 2018).
Vecchio, E. A., White, P. J. & May, L. T. The adenosine A2B G protein-coupled receptor: recent advances and therapeutic implications. Pharmacol. Therapeutics 198, 20–33 (2019).
Lappas, C. M., Rieger, J. M. & Linden, J. A2A adenosine receptor induction inhibits IFN-γ production in murine CD4+ T cells. J. Immunol. 174, 1073–1080 (2005).
Linnemann, C. et al. Adenosine regulates CD8 T-cell priming by inhibition of membrane-proximal T-cell receptor signalling. Immunology 128, e728–e737 (2009).
Bjørgo, E. & Taskén, K. Novel mechanism of signaling by CD28. Immunol. Lett. 129, 1–6 (2010).
Zhang, H. et al. Adenosine acts through A2 receptors to inhibit IL-2-induced tyrosine phosphorylation of STAT5 in T lymphocytes: role of cyclic adenosine 3’,5’-monophosphate and phosphatases. J. Immunol. 173, 932–944 (2004).
Sorrentino, C. et al. Adenosine A2A receptor stimulation inhibits TCR-induced Notch1 activation in CD8+ T-cells. Front. Immunol. 10, (2019).
Mastelic-Gavillet, B. et al. Adenosine mediates functional and metabolic suppression of peripheral and tumor-infiltrating CD8+ T cells. J. Immunother. Cancer 7, 257 (2019).
Raskovalova, T. et al. Inhibition of cytokine production and cytotoxic activity of human antimelanoma specific CD8+ and CD4+ T lymphocytes by adenosine-protein kinase A type I signaling. Cancer Res. 67, 5949–5956 (2007).
Romio, M. et al. Extracellular purine metabolism and signaling of CD73-derived adenosine in murine Treg and Teff cells. Am. J. Physiol. 301, C530–C539 (2011).
Csóka, B. et al. Adenosine A2A receptor activation inhibits T helper 1 and T helper 2 cell development and effector function. FASEB J. 22, 3491–3499 (2008).
Leone, R. D. et al. Inhibition of the adenosine A2a receptor modulates expression of T cell coinhibitory receptors and improves effector function for enhanced checkpoint blockade and ACT in murine cancer models. Cancer Immunol. Immunother. 67, 1271–1284 (2018).
Ohta, A. et al. The development and immunosuppressive functions of CD4+ CD25+ FoxP3+ regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway. Front. Immunol. 3, 190 (2012).
Zarek, P. E. et al. A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 111, 251–259 (2008).
Deaglio, S. et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204, 1257–1265 (2007).
Borsellino, G. et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110, 1225–1232 (2007).
Mandapathil, M. et al. Generation and accumulation of immunosuppressive adenosine by human CD4+CD25highFOXP3+ regulatory T cells. J. Biol. Chem. 285, 7176–7186 (2010).
Schuler, P. J. et al. Human CD4+ CD39+ regulatory T cells produce adenosine upon co-expression of surface CD73 or contact with CD73+ exosomes or CD73+ cells. Clin. Exp. Immunol. 177, 531–543 (2014).
Ehrentraut, H., Westrich, J. A., Eltzschig, H. K. & Clambey, E. T. Adora2b adenosine receptor engagement enhances regulatory T cell abundance during endotoxin-induced pulmonary inflammation. PLoS One 7, e32416 (2012).
Kinsey, G. R. et al. Autocrine adenosine signaling promotes regulatory T cell-mediated renal protection. J. Am. Soc. Nephrol. 23, 1528–1537 (2012).
Minguet, S. et al. Adenosine and cAMP are potent inhibitors of the NF-κB pathway downstream of immunoreceptors. Eur. J. Immunol. 35, 31–41 (2005).
Young, A. et al. A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment. Cancer Res. 78, 1003–1016 (2018).
Raskovalova, T., Lokshin, A., Huang, X., Jackson, E. K. & Gorelik, D. E. Adenosine-mediated inhibition of cytotoxic activity and cytokine production by IL-2/NKp46-activated NK cells: involvement of protein kinase A isozyme I (PKA I). Immunol. Res. 36, 91–99 (2006).
Raskovalova, T. et al. Gs protein-coupled adenosine receptor signaling and lytic function of activated NK cells. J. Immunol. 175, 4383–4391 (2005).
Wallace, K. L. & Linden, J. Adenosine A2A receptors induced on iNKT and NK cells reduce pulmonary inflammation and injury in mice with sickle cell disease. Blood 116, 5010–5020 (2010).
Csóka, B. et al. Adenosine receptors differentially regulate type 2 cytokine production by IL-33–activated bone marrow cells, ILC2s, and macrophages. FASEB J. 32, 829–837 (2017).
Hazenberg, M. D. et al. Human ectoenzyme-expressing ILC3: immunosuppressive innate cells that are depleted in graft-versus-host disease. Blood Adv. 3, 3650–3660 (2019).
Cohen, H. B., Ward, A., Hamidzadeh, K., Ravid, K. & Mosser, D. M. IFN-γ prevents adenosine receptor (A2bR) upregulation to sustain the macrophage activation response. J. Immunol. 195, 3828–3837 (2015).
Ramanathan, M. et al. Differential regulation of HIF-1α isoforms in murine macrophages by TLR4 and adenosine A2A receptor agonists. J. Leukoc. Biol. 86, 681–689 (2009).
Csóka, B. et al. Adenosine promotes alternative macrophage activation via A2A and A2B receptors. FASEB J. 26, 376–386 (2012).
Ferrante, C. J. et al. The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor alpha (IL-4Ralpha) signaling. Inflammation 36, 921–931 (2013).
Novitskiy, S. V. et al. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 112, 1822–1831 (2008).
Challier, J., Bruniquel, D., Sewell, A. K. & Laugel, B. Adenosine and cAMP signalling skew human dendritic cell differentiation towards a tolerogenic phenotype with defective CD8+ T-cell priming capacity. Immunology 138, 402–410 (2013).
Yago, T. et al. Multi-inhibitory effects of A2A adenosine receptor signaling on neutrophil adhesion under flow. J. Immunol. 195, 3880–3889 (2015).
Fredholm, B. B., Zhang, Y. & van der Ploeg, I. Adenosine A2A receptors mediate the inhibitory effect of adenosine on formyl-Met-Leu-Phe-stimulated respiratory burst in neutrophil leucocytes. Naunyn Schmiedebergs Arch. Pharmacol. 354, 262–267 (1996).
Gao, Z.-G. & Jacobson, K. A. Purinergic signaling in mast cell degranulation and asthma. Front. Pharmacol. 8, 947 (2017).
Pellegatti, P. et al. Increased level of extracellular ATP at tumor sites: in vivo imaging with plasma membrane luciferase. PLoS One 3, e2599 (2008).
Kroemer, G., Galluzzi, L., Kepp, O. & Zitvogel, L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51–72 (2013).
Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors. Nat. Med. 15, 1170–1178 (2009).
Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573–1577 (2011).
Ma, Y. et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 38, 729–741 (2013).
Li, X.-Y. et al. Targeting CD39 in cancer reveals an extracellular ATP- and inflammasome-driven tumor immunity. Cancer Discov. 9, 1754–1773 (2019).
Yan, J. et al. Control of metastases via myeloid CD39 and NK cell effector function. Cancer Immunol. Res. 8, 356–367 (2020).
Allard, B., Beavis, P. A., Darcy, P. K. & Stagg, J. Immunosuppressive activities of adenosine in cancer. Curr. Opin. Pharmacol. 29, 7–16 (2016).
Allard, B., Longhi, M. S., Robson, S. C. & Stagg, J. The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol. Rev. 276, 121–144 (2017).
Vijayan, D., Young, A., Teng, M. W. L. & Smyth, M. J. Targeting immunosuppressive adenosine in cancer. Nat. Rev. Cancer 17, 765 (2017).
Clayton, A., Al-Taei, S., Webber, J., Mason, M. D. & Tabi, Z. Cancer exosomes express CD39 and CD73, which suppress T cells through adenosine production. J. Immunol. 187, 676–683 (2011).
Houthuys, E. et al. EOS100850, an insurmountable and non-brain penetrant A2A receptor antagonist, inhibits adenosine-mediated T cell suppression, demonstrates anti-tumor activity and exhibits best-in class characteristics [abstract LB-291]. Cancer Res. 78, LB-291 (2018).
Hatfield, S. M. et al. Systemic oxygenation weakens the hypoxia and hypoxia inducible factor 1α-dependent and extracellular adenosine-mediated tumor protection. J. Mol. Med. 92, 1283–1292 (2014).
Eltzschig, H. K. et al. Central role of Sp1-regulated CD39 in hypoxia/ischemia protection. Blood 113, 224–232 (2009).
Synnestvedt, K. et al. Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J. Clin. Invest. 110, 993–1002 (2002).
Kong, T., Westerman, K. A., Faigle, M., Eltzschig, H. K. & Colgan, S. P. HIF-dependent induction of adenosine A2B receptor in hypoxia. FASEB J. 20, 2242–2250 (2006).
Ahmad, A. et al. Adenosine A2A receptor is a unique angiogenic target of HIF-2alpha in pulmonary endothelial cells. Proc. Natl Acad. Sci. USA 106, 10684–10689 (2009).
Bowser, J. L., Lee, J. W., Yuan, X. & Eltzschig, H. K. The hypoxia-adenosine link during inflammation. J. Appl. Physiol. 123, 1303–1320 (2017).
Hatfield, S. M. et al. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci. Transl. Med. 7, 277ra30 (2015).
Ryzhov, S. V. et al. Role of TGF-β signaling in generation of CD39+ CD73+ myeloid cells in tumors. J. Immunol. 193, 3155–3164 (2014).
Regateiro, F. S. et al. Generation of anti-inflammatory adenosine by leukocytes is regulated by TGF-β. Eur. J. Immunol. 41, 2955–2965 (2011).
Li, J. et al. CD39/CD73 upregulation on myeloid-derived suppressor cells via TGF-β-mTOR-HIF-1 signaling in patients with non-small cell lung cancer. Oncoimmunology 6, e1320011 (2017).
Lawrence, R. T. et al. The proteomic landscape of triple-negative breast cancer. Cell Rep. 11, 630–644 (2015).
Sunaga, N. et al. Knockdown of oncogenic KRAS in non-small cell lung cancers suppresses tumor growth and sensitizes tumor cells to targeted therapy. Mol. Cancer Ther. 10, 336–346 (2011).
Inoue, Y. et al. Prognostic impact of CD73 and A2A adenosine receptor expression in non-small-cell lung cancer. Oncotarget 8, 8738–8751 (2017).
Udyavar, A. R. et al. Altered pan-Ras pathway and activating mutations in EGFR result in elevated CD73 in multiple cancers [abstract 4980]. Cancer Res. 79 (Suppl.), 4980–4980 (2019).
Reinhardt, J. et al. MAPK signaling and inflammation link melanoma phenotype switching to induction of CD73 during immunotherapy. Cancer Res. 77, 4697–4709 (2017).
Turcotte, M. et al. CD73 promotes resistance to HER2/ErbB2 antibody therapy. Cancer Res. 77, 5652–5663 (2017).
García-Rocha, R. et al. Cervical cancer cells produce TGF-β1 through the CD73-adenosine pathway and maintain CD73 expression through the autocrine activity of TGF-β1. Cytokine 118, 71–79 (2019).
Spychala, J. & Kitajewski, J. Wnt and β-catenin signaling target the expression of ecto-5′-nucleotidase and increase extracellular adenosine generation. Exp. Cell Res. 296, 99–108 (2004).
Turcotte, M. et al. CD73 is associated with poor prognosis in high-grade serous ovarian cancer. Cancer Res. 75, 4494–4503 (2015).
Lupia, M. et al. CD73 regulates stemness and epithelial-mesenchymal transition in ovarian cancer-initiating cells. Stem Cell Rep. 10, 1412–1425 (2018).
Song, Y., Song, C. & Yang, S. Tumor-suppressive function of miR-30d-5p in prostate cancer cell proliferation and migration by targeting NT5E. Cancer Biother. Radiopharm. 33, 203–211 (2018).
Wang, H. et al. NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity. Br. J. Cancer 106, 1446–1452 (2012).
Spychala, J. et al. Role of estrogen receptor in the regulation of ecto-5’-nucleotidase and adenosine in breast cancer. Clin. Cancer Res. 10, 708–717 (2004).
Zhu, J. et al. CD73/NT5E is a target of miR-30a-5p and plays an important role in the pathogenesis of non-small cell lung cancer. Mol. Cancer 16, 34 (2017).
Bonnin, N. et al. MiR-422a promotes loco-regional recurrence by targeting NT5E/CD73 in head and neck squamous cell carcinoma. Oncotarget 7, 44023–44038 (2016).
Mousavi, S., Panjehpour, M., Izadpanahi, M. H. & Aghaei, M. Expression of adenosine receptor subclasses in malignant and adjacent normal human prostate tissues. Prostate 75, 735–747 (2015).
Horenstein, A. L. et al. Adenosine generated in the bone marrow niche through a CD38-mediated pathway correlates with progression of human myeloma. Mol. Med. 22, 694–704 (2016).
Chen, L. et al. CD38-mediated immunosuppression as a mechanism of tumor cell escape from PD-1/PD-L1 blockade. Cancer Discov. 8, 1156–1175 (2018).
Morandi, F. et al. A non-canonical adenosinergic pathway led by CD38 in human melanoma cells induces suppression of T cell proliferation. Oncotarget 6, 25602–25618 (2015).
Kukulski, F. et al. Comparative hydrolysis of P2 receptor agonists by NTPDases 1, 2, 3 and 8. Purinergic Signal. 1, 193–204 (2005).
Ma, X.-L. et al. CD73 promotes hepatocellular carcinoma progression and metastasis via activating PI3K/AKT signaling by inducing Rap1-mediated membrane localization of P110β and predicts poor prognosis. J. Hematol. Oncol. 12, 37 (2019).
Shi, L. et al. Adenosine interaction with adenosine receptor A2a promotes gastric cancer metastasis by enhancing PI3K-AKT-mTOR signaling. Mol. Biol. Cell 30, 2527–2534 (2019).
Mittal, D. et al. Adenosine 2B receptor expression on cancer cells promotes metastasis. Cancer Res. 76, 4372–4382 (2016).
Yi, Y. et al. Blockade of adenosine A2b receptor reduces tumor growth and migration in renal cell carcinoma. J. Cancer 11, 421–431 (2020).
Zhou, Y. et al. The adenosine A2b receptor promotes tumor progression of bladder urothelial carcinoma by enhancing MAPK signaling pathway. Oncotarget 8, 48755–48768 (2017).
Zhi, X. et al. RNAi-mediated CD73 suppression induces apoptosis and cell-cycle arrest in human breast cancer cells. Cancer Sci. 101, 2561–2569 (2010).
Zhou, J. Z. et al. Differential impact of adenosine nucleotides released by osteocytes on breast cancer growth and bone metastasis. Oncogene 34, 1831–1842 (2015).
Beavis, P. A. et al. Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proc. Natl Acad. Sci. USA 110, 14711–14716 (2013).
Desmet, C. J. et al. Identification of a pharmacologically tractable Fra-1/ADORA2B axis promoting breast cancer metastasis. Proc. Natl Acad. Sci. USA 110, 5139–5144 (2013).
Ntantie, E. et al. An adenosine-mediated signaling pathway suppresses prenylation of the GTPase Rap1B and promotes cell scattering. Sci. Signal. 6, ra39 (2013).
Pastushenko, I. & Blanpain, C. EMT transition states during tumor progression and metastasis. Trends Cell Biol. 29, 212–226 (2019).
Lan, J. et al. Hypoxia-inducible factor 1-dependent expression of adenosine receptor 2B promotes breast cancer stem cell enrichment. Proc. Natl Acad. Sci. USA 115, E9640–E9648 (2018).
Liu, T. et al. The HIF-2alpha dependent induction of PAP and adenosine synthesis regulates glioblastoma stem cell function through the A2B adenosine receptor. Int. J. Biochem. Cell Biol. 49, 8–16 (2014).
Ma, X.-L. et al. CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma. J. Hematol. Oncol. 13, 11 (2020).
Xiong, L., Wen, Y., Miao, X. & Yang, Z. NT5E and FcGBP as key regulators of TGF-1-induced epithelial-mesenchymal transition (EMT) are associated with tumor progression and survival of patients with gallbladder cancer. Cell Tissue Res. 355, 365–374 (2014).
Sidders, B. et al. Adenosine signalling is prognostic for cancer outcome and has predictive utility for immunotherapeutic response. Clin. Cancer Res. 26, 2176–2187 (2020).
Sadej, R. & Skladanowskic, A. C. Dual, enzymatic and non-enzymatic, function of ecto-5’-nucleotidase (eN, CD73) in migration and invasion of A375 melanoma cells. Acta Biochim. Pol. 59, 647–652 (2012).
Gao, Z. et al. CD73 promotes proliferation and migration of human cervical cancer cells independent of its enzyme activity. BMC Cancer 17, 135 (2017).
Zhou, L. et al. The distinct role of CD73 in the progression of pancreatic cancer. J. Mol. Med. 97, 803–815 (2019).
Yu, M. et al. CD73 on cancer-associated fibroblasts enhanced by the A2B-mediated feedforward circuit enforces an immune checkpoint. Nat. Commun. 11, 515 (2020).
Costa, A. et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell 33, 463–479.e10 (2018).
Mediavilla-Varela, M. et al. Antagonism of adenosine A2A receptor expressed by lung adenocarcinoma tumor cells and cancer associated fibroblasts inhibits their growth. Cancer Biol. Ther. 14, 860–868 (2013).
Sorrentino, C., Miele, L., Porta, A., Pinto, A. & Morello, S. Activation of the A2B adenosine receptor in B16 melanomas induces CXCL12 expression in FAP-positive tumor stromal cells, enhancing tumor progression. Oncotarget 7, 64274–64288 (2016).
Thompson, L. F. et al. Crucial role for Ecto-5′-nucleotidase (CD73) in vascular leakage during hypoxia. J. Exp. Med. 200, 1395–1405 (2004).
Airas, L., Niemelä, J. & Jalkanen, S. CD73 engagement promotes lymphocyte binding to endothelial cells Via a lymphocyte function-associated antigen-1-dependent mechanism. J. Immunol. 165, 5411–5417 (2000).
Takedachi, M. et al. CD73-generated adenosine restricts lymphocyte migration into draining lymph nodes. J. Immunol. 180, 6288–6296 (2008).
Liu, Z. et al. Endothelial adenosine A2a receptor-mediated glycolysis is essential for pathological retinal angiogenesis. Nat. Commun. 8, 584 (2017).
Desai, A. Adenosine A2A receptor stimulation increases angiogenesis by down-regulating production of the antiangiogenic matrix protein thrombospondin 1. Mol. Pharmacol. 67, 1406–1413 (2005).
Allard, B. et al. Anti-CD73 therapy impairs tumor angiogenesis. Int. J. Cancer 134, 1466–1473 (2014).
Wang, L. et al. Ecto-5′-nucleotidase (CD73) promotes tumor angiogenesis. Clin. Exp. Metastasis 30, 671–680 (2013).
Siu, L. L. et al. Preliminary phase 1 profile of BMS-986179, an anti-CD73 antibody, in combination with nivolumab in patients with advanced solid tumors [abstract CT180]. Cancer Res. 78 (Suppl.), CT180–CT180 (2018).
Allard, B. et al. Adenosine A2a receptor promotes lymphangiogenesis and lymph node metastasis. Oncoimmunology 8, 1601481 (2019).
Hammami, A., Allard, D., Allard, B. & Stagg, J. Targeting the adenosine pathway for cancer immunotherapy. Semin. Immunol. 42, 101304 (2019).
Vigano, S. et al. Targeting adenosine in cancer immunotherapy to enhance T-cell function. Front. Immunol. 10, 925 (2019).
Mittal, D. et al. Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer Res. 74, 3652–3658 (2014).
Zhang, H. et al. The role of NK cells and CD39 in the immunological control of tumor metastases. Oncoimmunology 8, e1593809 (2019).
Perrot, I. et al. Blocking antibodies targeting the CD39/CD73 immunosuppressive pathway unleash immune responses in combination cancer therapies. Cell Rep. 27, 2411–2425.e9 (2019).
Cekic, C., Day, Y.-J., Sag, D. & Linden, J. Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironment. Cancer Res. 74, 7250–7259 (2014).
Cekic, C. et al. Adenosine A2B receptor blockade slows growth of bladder and breast tumors. J. Immunol. 188, 198–205 (2012).
Ryzhov, S. et al. Host A2B adenosine receptors promote carcinoma growth. Neoplasia 10, 987–995 (2008).
Ryzhov, S. et al. Adenosinergic regulation of the expansion and immunosuppressive activity of CD11b+ Gr1+ cells. J. Immunol. 187, 6120–6129 (2011).
Sorrentino, C., Miele, L., Porta, A., Pinto, A. & Morello, S. Myeloid-derived suppressor cells contribute to A2B adenosine receptor-induced VEGF production and angiogenesis in a mouse melanoma model. Oncotarget 6, 27478–27489 (2015).
Iannone, R., Miele, L., Maiolino, P., Pinto, A. & Morello, S. Blockade of A2b adenosine receptor reduces tumor growth and immune suppression mediated by myeloid-derived suppressor cells in a mouse model of melanoma. Neoplasia 15, 1400–1409 (2013).
Gourdin, N. et al. Autocrine adenosine regulates tumor polyfunctional CD73+ CD4+ effector T cells devoid of immune checkpoints. Cancer Res. 78, 3604–3618 (2018).
Beavis, P. A. et al. Adenosine receptor 2A blockade increases the efficacy of anti–PD-1 through enhanced antitumor T-cell responses. Cancer Immunol. Res. 3, 506–517 (2015).
Himer, L. et al. Adenosine A2A receptor activation protects CD4+ T lymphocytes against activation-induced cell death. FASEB J. 24, 2631–2640 (2010).
Cekic, C. & Linden, J. Adenosine A2A receptors intrinsically regulate CD8+ T cells in the tumor microenvironment. Cancer Res. 74, 7239–7249 (2014).
Cekic, C., Sag, D., Day, Y.-J. & Linden, J. Extracellular adenosine regulates naive T cell development and peripheral maintenance. J. Exp. Med. 210, 2693–2706 (2013).
Maj, T. et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat. Immunol. 18, 1332–1341 (2017).
Mandapathil, M. et al. Increased ectonucleotidase expression and activity in regulatory T cells of patients with head and neck cancer. Clin. Cancer Res. 15, 6348–6357 (2009).
Mandapathil, M. et al. Adenosine and prostaglandin E2 cooperate in the suppression of immune responses mediated by adaptive regulatory T cells. J. Biol. Chem. 285, 27571–27580 (2010).
Kaji, W., Tanaka, S., Tsukimoto, M. & Kojima, S. Adenosine A2B receptor antagonist PSB603 suppresses tumor growth and metastasis by inhibiting induction of regulatory T cells. J. Toxicol. Sci. 39, 191–198 (2014).
Loi, S. et al. CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer. Proc. Natl Acad. Sci. USA 110, 11091–11096 (2013).
Young, A. et al. Targeting adenosine in BRAF-mutant melanoma reduces tumor growth and metastasis. Cancer Res. 77, 4684–4696 (2017).
Allard, D., Chrobak, P., Allard, B., Messaoudi, N. & Stagg, J. Targeting the CD73-adenosine axis in immuno-oncology. Immunol. Lett. 205, 31–39 (2019).
Koivisto, M. K. et al. Cell-type-specific CD73 expression is an independent prognostic factor in bladder cancer. Carcinogenesis 40, 84–92 (2019).
Bowser, J. L. et al. Loss of CD73-mediated actin polymerization promotes endometrial tumor progression. J. Clin. Invest. 126, 220–238 (2016).
Leclerc, B. G. et al. CD73 expression is an independent prognostic factor in prostate cancer. Clin. Cancer Res. 22, 158–166 (2016).
Jiang, T. et al. Comprehensive evaluation of NT5E/CD73 expression and its prognostic significance in distinct types of cancers. BMC Cancer 18, 267 (2018).
Wang, R., Zhang, Y., Lin, X., Gao, Y. & Zhu, Y. Prognositic value of CD73-adenosinergic pathway in solid tumor: A meta-analysis and systematic review. Oncotarget 8, 57327–57336 (2017).
Buisseret, L. et al. Clinical significance of CD73 in triple-negative breast cancer: multiplex analysis of a phase III clinical trial. Ann. Oncol. 29, 1056–1062 (2018).
Morello, S. et al. Soluble CD73 as biomarker in patients with metastatic melanoma patients treated with nivolumab. J. Transl. Med. 15, 244 (2017).
Zhang, F. et al. Specific decrease in B-Cell-derived extracellular vesicles enhances post-chemotherapeutic CD8+ T cell responses. Immunity 50, 738–750.e7 (2019).
Ibrahim, S. et al. CD38 expression as an important prognostic factor in B-cell chronic lymphocytic leukemia. Blood 98, 181–186 (2001).
Perry, C. et al. Increased CD39 expression on CD4+ T lymphocytes has clinical and prognostic significance in chronic lymphocytic leukemia. Ann. Hematol. 91, 1271–1279 (2012).
Pinna, A. Adenosine A2A receptor antagonists in Parkinson’s disease: progress in clinical trials from the newly approved istradefylline to drugs in early development and those already discontinued. CNS Drugs 28, 455–474 (2014).
Hay, C. M. et al. Targeting CD73 in the tumor microenvironment with MEDI9447. Oncoimmunology 5, e1208875 (2016).
Young, A. et al. Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor immune responses. Cancer Cell 30, 391–403 (2016).
Schindler, U. et al. AB680, a potent and selective CD73 small molecule inhibitor, reverses the AMP/adenosine-mediated impairment of immune effector cell activation by immune checkpoint inhibitors. Eur. J. Cancer 92 (Suppl. 1), S14 (2018).
Lee, C. C. et al. Reversal of adenosine-mediated immune suppression by CB-708, an orally bioavailable and potent small molecule inhibitor of CD73 [abstract 4134]. Cancer Res. 79 (Suppl.), 4134–4134 (2019).
Fong, L. et al. Adenosine A2A receptor blockade as an immunotherapy for treatment-refractory renal cell cancer. Cancer Discov. 10, 40–53 (2020).
Harshman, L. C. et al. Adenosine receptor blockade with ciforadenant +/– atezolizumab in advanced metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol. 38, 129–129 (2020).
Bendell, J. et al. Evidence of immune activation in the first-in-human Phase Ia dose escalation study of the adenosine 2a receptor antagonist, AZD4635, in patients with advanced solid tumors [abstract CT026]. Cancer Res. 79 (Suppl.), CT026–CT026 (2019).
Chiappori, A. et al. Phase I/II study of the A2AR antagonist NIR178 (PBF-509), an oral immunotherapy, in patients (pts) with advanced NSCLC. J. Clin. Oncol. 36, 9089–9089 (2018).
Seitz, L. et al. Safety, tolerability, and pharmacology of AB928, a novel dual adenosine receptor antagonist, in a randomized, phase 1 study in healthy volunteers. Invest. New Drugs 37, 711–721 (2019).
Overman, M. J. et al. Safety, efficacy and pharmacodynamics (PD) of MEDI9447 (oleclumab) alone or in combination with durvalumab in advanced colorectal cancer (CRC) or pancreatic cancer (panc). J. Clin. Oncol. 36, 4123–4123 (2018).
Luke, J. J. et al. Immunobiology and clinical activity of CPI-006, an anti-CD73 antibody with immunomodulating properties in a phase 1/1b trial in advanced cancers. https://www.corvuspharma.com/file.cfm/23/docs/SITCFINAL_2019_11052019_vs1.pdf (2019).
Powderly, J. et al. Phase 1 evaluation of AB928, a novel dual adenosine receptor antagonist, combined with chemotherapy or AB122 (anti-PD-1) in patients (pts) with advanced malignancies. Ann. Oncol. 30 (Suppl. 5), v475–v532 (2019).
DiRenzo, D. et al. AB928, a dual antagonist of the A2aR and A2bR adenosine receptors, relieves adenosine-mediated immune suppression [abstract A162]. Cancer Immunol. Res. 7 (Suppl.), A162–A162 (2019).
Galluzzi, L., Buqué, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunogenic cell death in cancer and infectious disease. Nat. Rev. Immunol. 17, 97–111 (2017).
Maurer, C. et al. 195TiPSYNERGY: Phase I and randomized phase II trial to investigate the addition of the anti-CD73 antibody oleclumab to durvalumab, paclitaxel and carboplatin for previously untreated, locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC). Ann. Oncol. 30 (Suppl. 3), ii47–iii64 (2019).
Nakamura, K. et al. Targeting an adenosine-mediated “don’t eat me signal” augments anti-lymphoma immunity by anti-CD20 monoclonal antibody. Leukemia https://doi.org/10.1038/s41375-020-0811-3 (2020).
Tokunaga, R. et al. Prognostic effect of adenosine-related genetic variants in metastatic colorectal cancer treated with bevacizumab-based chemotherapy. Clin. Colorectal Cancer 18, e8–e19 (2019).
Beavis, P. A. et al. Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy. J. Clin. Invest. 127, 929–941 (2017).
Allard, B., Pommey, S., Smyth, M. J. & Stagg, J. Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin. Cancer Res. 19, 5626–5635 (2013).
Beavis, P. A. et al. Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor T-cell responses. Cancer Immunol. Res. 3, 506–517 (2015).
Chen, S. et al. CD73 expression on effector T cells sustained by TGF-β facilitates tumor resistance to anti-4-1BB/CD137 therapy. Nat. Commun. 10, 150 (2019).
Wirsdörfer, F. et al. Extracellular adenosine production by ecto-5’-nucleotidase (CD73) enhances radiation-induced lung fibrosis. Cancer Res. 76, 3045–3056 (2016).
Wennerberg, E. et al. CD73 blockade promotes dendritic cell infiltration of irradiated tumors and tumor rejection. Cancer Immunol. Res. 8, 465–478 (2020).
Lohman, A. W., Billaud, M. & Isakson, B. E. Mechanisms of ATP release and signalling in the blood vessel wall. Cardiovascular Res. 95, 269–280 (2012).
Enjyoji, K. et al. Targeted disruption of cd39 /ATP diphosphohydrolase results in disordered hemostasis and thromboregulation. Nat. Med. 5, 1010–1017 (1999).
Yadav, V. et al. Ectonucleotidase tri(di)phosphohydrolase-1 (ENTPD-1) disrupts inflammasome/interleukin 1β-driven venous thrombosis. J. Clin. Invest. 129, 2872–2877 (2019).
Berwick, Z. C. et al. Contribution of adenosine A2A and A2B receptors to ischemic coronary dilation: role of KV and KATP channels. Microcirculation 17, 600–607 (2010).
St. Hilaire, C. et al. NT5E mutations and arterial calcifications. N. Engl. J. Med. 364, 432–442 (2011).
Jin, H. et al. Increased activity of TNAP compensates for reduced adenosine production and promotes ectopic calcification in the genetic disease ACDC. Sci. Signal. 9, ra121 (2016).
Kishore, B. K., Robson, S. C. & Dwyer, K. M. CD39-adenosinergic axis in renal pathophysiology and therapeutics. Purinergic Signal. 14, 109–120 (2018).
Rabadi, M. M. & Lee, H. T. Adenosine receptors and renal ischaemia reperfusion injury. Acta Physiologica 213, 222–231 (2015).
Sung, S.-S. J. et al. Proximal tubule CD73 is critical in renal ischemia-reperfusion injury protection. J. Am. Soc. Nephrol. 28, 888–902 (2017).
Seethapathy, H. et al. The incidence, causes, and risk factors of acute kidney injury in patients receiving immune checkpoint inhibitors. Clin. J. Am. Soc. Nephrol. 14, 1692–1700 (2019).
Perruzza, L. et al. T follicular helper cells promote a beneficial gut ecosystem for host metabolic homeostasis by sensing microbiota-derived extracellular ATP. Cell Rep. 18, 2566–2575 (2017).
Friedman, D. J. et al. From the cover: CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease. Proc. Natl Acad. Sci. USA 106, 16788–16793 (2009).
Patel, N. et al. A2B adenosine receptor induces protective antihelminth type 2 immune responses. Cell Host Microbe 15, 339–350 (2014).
Kao, D. J. et al. Intestinal epithelial ecto-5′-nucleotidase (CD73) regulates intestinal colonization and infection by nontyphoidal salmonella. Infect. Immun. 85, e01022-16 (2017).
Aherne, C. M. et al. Epithelial-specific A2B adenosine receptor signaling protects the colonic epithelial barrier during acute colitis. Mucosal Immunol. 8, 1324–1338 (2015).
Kurtz, C. C. et al. Extracellular adenosine regulates colitis through effects on lymphoid and nonlymphoid cells. Am. J. Physiol. Gastrointest. Liver Physiol. 307, G338–G346 (2014).
Mabley, J. et al. The adenosine A3 receptor agonist, N6-(3-iodobenzyl)-adenosine-5’-N-methyluronamide, is protective in two murine models of colitis. Eur. J. Pharmacol. 466, 323–329 (2003).
Vuerich, M., Robson, S. C. & Longhi, M. S. Ectonucleotidases in intestinal and hepatic inflammation. Front. Immunol. 10, 507 (2019).
Enjyoji, K. et al. Deletion of cd39/entpd1 results in hepatic insulin resistance. Diabetes 57, 2311–2320 (2008).
Csóka, B. et al. A2A adenosine receptors control pancreatic dysfunction in high-fat-diet-induced obesity. FASEB J. 31, 4985–4997 (2017).
Zhou, J. et al. Mice lacking adenosine 2A receptor reveal increased severity of MCD-induced NASH. J. Endocrinol. 243, 199–209 (2019).
Cai, Y. et al. Disruption of adenosine 2A receptor exacerbates NAFLD through increasing inflammatory responses and SREBP1c activity. Hepatology 68, 48–61 (2018).
Peng, Z. et al. Ecto-5′-nucleotidase (CD73) -mediated extracellular adenosine production plays a critical role in hepatic fibrosis. FASEB J. 22, 2263–2272 (2008).
Chan, E. S. L. et al. Adenosine A2A receptors play a role in the pathogenesis of hepatic cirrhosis. Br. J. Pharmacol. 148, 1144–1155 (2006).
Peng, Z. et al. Adenosine signaling contributes to ethanol-induced fatty liver in mice. J. Clin. Invest. 119, 582–594 (2009).
Mediero, A., Wilder, T., Shah, L. & Cronstein, B. N. Adenosine A2A receptor (A2AR) stimulation modulates expression of semaphorins 4D and 3A, regulators of bone homeostasis. FASEB J. 32, 3487–3501 (2018).
Mediero, A., Wilder, T., Perez-Aso, M. & Cronstein, B. N. Direct or indirect stimulation of adenosine A2A receptors enhances bone regeneration as well as bone morphogenetic protein-2. FASEB J. 29, 1577–1590 (2015).
He, W. & Cronstein, B. N. Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling. Purinergic Signal. 8, 327–337 (2012).
Shih, Y.-R. V. et al. Dysregulation of ectonucleotidase-mediated extracellular adenosine during postmenopausal bone loss. Sci. Adv. 5, eaax1387 (2019).
Takedachi, M. et al. CD73-generated adenosine promotes osteoblast differentiation. J. Cell Physiol. 227, 2622–2631 (2012).
Corciulo, C., Wilder, T. & Cronstein, B. N. Adenosine A2B receptors play an important role in bone homeostasis. Purinergic Signal. 12, 537–547 (2016).
Ryan, R., Cleary, S., O’Shaughnessy, K. & Yasmin. An NT5E gene polymorphism associates with low bone mineral density in chronic kidney disease patients. J. Clin. Res. Med. 1, 1–9 (2018).
Cunha, R. A. How does adenosine control neuronal dysfunction and neurodegeneration? J. Neurochem. 139, 1019–1055 (2016).
Johansson, B. et al. Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1 receptor. Proc. Natl Acad. Sci. USA 98, 9407–9412 (2001).
Aoyama, S., Kase, H. & Borrelli, E. Rescue of locomotor impairment in dopamine D2 receptor-deficient mice by an adenosine A2A receptor antagonist. J. Neurosci. 20, 5848–5852 (2000).
Kim, D.-G. & Bynoe, M. S. A2A adenosine receptor regulates the human blood-brain barrier permeability. Mol. Neurobiol. 52, 664–678 (2015).
Wei, C. J., Li, W. & Chen, J.-F. Normal and abnormal functions of adenosine receptors in the central nervous system revealed by genetic knockout studies. Biochim. Biophys. Acta 1808, 1358–1379 (2011).
Hinz, S. et al. Adenosine A2A receptor ligand recognition and signaling is blocked by A2B receptors. Oncotarget 9, 13593–13611 (2018).
Allard, D., Allard, B. & Stagg, J. On the mechanism of anti-CD39 immune checkpoint therapy. J. Immunother. Cancer 8, (2020).
Borges da Silva, H. et al. The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells. Nature 559, 264–268 (2018).
Sadej, R. et al. Tenascin C interacts with Ecto-5′-nucleotidase (eN) and regulates adenosine generation in cancer cells. Biochim. Biophys. Acta 1782, 35–40 (2008).
Garavaglia, S. et al. The high-resolution crystal structure of periplasmic Haemophilus influenzae NAD nucleotidase reveals a novel enzymatic function of human CD73 related to NAD metabolism. Biochem. J. 441, 131–141 (2012).
Wilk, A. et al. Extracellular NAD+ enhances PARP-dependent DNA repair capacity independently of CD73 activity. Sci. Rep. 10, 651 (2020).
Acknowledgements
The work of D.A. is supported by a doctoral scholarship from the Fonds Recherche Santé – Québec. The work of J.S. is supported by research grants from the Canadian Institutes of Health Research, the Terry Fox Research Institute and the Canadian Cancer Society. J.S. acknowledges research support from the Jean-Guy Sabourin Research Chair in Pharmacology.
Author information
Authors and Affiliations
Contributions
D.A. and L.B. made substantial contributions to the discussion of content. B.A., D.A., L.B. and J.S. wrote the manuscript. B.A. and J.S. reviewed/edited the manuscript before submission and subsequently revised the manuscript. B.A. and D.A. designed the figures. D.A. and L.B. compiled the tables, and J.S. compiled the boxes.
Corresponding author
Ethics declarations
Competing interests
J.S. is a permanent member of the scientific advisory board and holds stocks of Surface Oncology. The other authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Reviewer information
Nature Reviews Clinical Oncology thanks the four anonymous reviewers for their contribution to the peer review of this work.
Related links
Xena: https://xena.ucsc.edu/
Xena Help Page: https://ucsc-xena.gitbook.io/project/how-do-i/tumor-vs-normal
Supplementary information
Rights and permissions
About this article
Cite this article
Allard, B., Allard, D., Buisseret, L. et al. The adenosine pathway in immuno-oncology. Nat Rev Clin Oncol 17, 611–629 (2020). https://doi.org/10.1038/s41571-020-0382-2
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41571-020-0382-2
This article is cited by
-
Unveiling the mechanisms and challenges of cancer drug resistance
Cell Communication and Signaling (2024)
-
Cancer cell metabolism and antitumour immunity
Nature Reviews Immunology (2024)
-
Purinergic pathways and their clinical use in the treatment of acute myeloid leukemia
Purinergic Signalling (2024)
-
Integrating bulk-RNA sequencing and single-cell sequencing analyses to characterize adenosine-enriched tumor microenvironment landscape and develop an adenosine-related prognostic signature predicting immunotherapy in lung adenocarcinoma
Functional & Integrative Genomics (2024)
-
Safety and pharmacokinetics of imaradenant (AZD4635) in Japanese patients with advanced solid malignancies: a phase I, open-label study
Cancer Chemotherapy and Pharmacology (2024)
