The ATP–adenosine pathway functions as a key modulator of innate and adaptive immunity within the tumour microenvironment. Consequently, multiple clinical strategies are being explored to target this pathway for the treatment of cancer; in particular, recent clinical data with CD73 antagonists and inhibitors of A2A receptors have demonstrated the therapeutic potential of modulating this pathway. Now, inhibitors of the ectonucleotidase CD39, the rate-limiting enzyme in the conversion of ATP to immunomodulatory adenosine, are entering clinical trials. Consequently, there is currently a focus on understanding the impact of CD39 enzymatic function on innate and adaptive immunity and how therapeutic modulation of this pathway alters their functional potential within the tumour microenvironment. Recent findings reveal multipronged mechanisms of action of CD39 antagonism that rely not only on preventing the accumulation of adenosine but also on the stabilization of pro-inflammatory extracellular ATP to restore antitumour immunity. Here, we review the impact of CD39 expression and ectonucleotidase activity on immunity with a focus on the setting of oncology. Additionally, we discuss the implications for immunotherapy strategies targeting CD39, including their inclusion in rational combination therapies.
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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). This foundational paper is the first to describe the immunosuppressive effect of adenosine receptor A 2A in vivo.
Huang, S., Apasov, S., Koshiba, M. & Sitkovsky, M. Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood 90, 1600–1610 (1997).
Wolberg, G., Zimmerman, T., Hiemstra, K., Winston, M. & Chu, L. Adenosine inhibition of lymphocyte-mediated cytolysis — possible role of cyclic adenosine monophosphate. Science 187, 957–959 (1975).
Ohta, A. et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc. Natl Acad. Sci. USA 103, 13132–13137 (2006).
Kaczmarek, E. et al. Identification and characterization of CD39/vascular ATP diphosphohydrolase. J. Biol. Chem. 271, 33116–33122 (1996).
Enjyoji, K. et al. Targeted disruption of CD39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation. Nat. Med. 5, 1010–1017 (1999).
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).
Jackson, S. W. et al. Disordered purinergic signaling inhibits pathological angiogenesis in CD39/ENTPD1-null mice. Am. J. Pathol. 171, 1395–1404 (2007).
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).
Hatfield, S., Veszeleiova, K., Steingold, J., Sethuraman, J. & Sitkovsky, M. Mechanistic justifications of systemic therapeutic oxygenation of tumors to weaken the hypoxia inducible factor 1α-mediated immunosuppression. Adv. Exp. Med. Biol. 1136, 113–121 (2019).
Vijayan, D., Young, A., Teng, M. W. L. & Smyth, M. J. Targeting immunosuppressive adenosine in cancer. Nat. Rev. Cancer 17, 709–724 (2017).
Young, A., Mittal, D., Stagg, J. & Smyth, M. J. Targeting cancer-derived adenosine: new therapeutic approaches. Cancer Discov. 4, 879–888 (2014).
Boison, D. & Yegutkin, G. G. Adenosine metabolism: emerging concepts for cancer therapy. Cancer Cell 36, 582–596 (2019).
Mascanfroni, I. D. et al. Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α. Nat. Med. 21, 638–646 (2015).
Takenaka, M. C. et al. Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39. Nat. Neurosci. 22, 729–740 2019).
Bastid, J. et al. Inhibition of CD39 enzymatic function at the surface of tumor cells alleviates their immunosuppressive activity. Cancer Immunol. Res. 3, 254–265 (2015).
Hayes, G. et al. CD39 is a promising therapeutic antibody target for the treatment of soft tissue sarcoma. Am. J. Transl. Res. 7, 1181–1188 (2015).
Pulte, D. et al. CD39 expression on T lymphocytes correlates with severity of disease in patients with chronic lymphocytic leukemia. Clin. Lymphoma Myeloma Leuk. 11, 367–372 (2011).
Hausler, S. F. 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. 60, 1405–1418 (2011).
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). This paper presents the first description of preclinical targeting of CD73 as a cancer immunotherapy.
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).
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).
Kjaergaard, J., Hatfield, S., Jones, G., Ohta, A. & Sitkovsky, M. A2A adenosine receptor gene deletion or synthetic A2A antagonist liberate tumor-reactive CD8+ T cells from tumor-induced immunosuppression. J. Immunol. 201, 782–791 (2018).
Turcotte, M. et al. CD73 promotes resistance to HER2/ErbB2 antibody therapy. Cancer Res. 77, 5652–5663 (2017).
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).
Young, A. et al. A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment. Cancer Res. 78, 1003–1016 (2018).
Cekic, C. & Linden, J. Adenosine A2A receptors intrinsically regulate CD8+ T cells in the tumor microenvironment. Cancer Res. 74, 7239–7249 (2014).
Young, A. et al. Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor immune responses. Cancer Cell 30, 391–403 (2016).
Li, X. Y. et al. Targeting CD39 in cancer reveals an extracellular ATP- and inflammasome-driven tumor mmunity. Cancer Discov. 9, 1754–1773 (2019). This study describes a mouse CD39 ecto-enzyme blocking antibody that triggers an eATP–P2X7–inflammasome–IL-18 axis that promotes intratumour immunity, overcomes anti-PD1 resistance and increases the efficacy of adoptive T cell transfer.
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).
Savio, L. E. B. et al. CD39 limits P2X7 receptor inflammatory signaling and attenuates sepsis-induced liver injury. J. Hepatol. 67, 716–726 (2017).
Cohen, H. B. et al. TLR stimulation initiates a CD39-based autoregulatory mechanism that limits macrophage inflammatory responses. Blood 122, 1935–1945 (2013).
MacKenzie, A. et al. Rapid secretion of interleukin-1β by microvesicle shedding. Immunity 15, 825–835 (2001).
Thomas, L. M. & Salter, R. D. Activation of macrophages by P2X7-induced microvesicles from myeloid cells is mediated by phospholipids and is partially dependent on TLR4. J. Immunol. 185, 3740–3749 (2010).
Soni, S. et al. ATP redirects cytokine trafficking and promotes novel membrane TNF signaling via microvesicles. FASEB J. 33, 6442–6455 (2019).
Elliott, M. R. et al. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461, 282–286 (2009).
Kronlage, M. et al. Autocrine purinergic receptor signaling is essential for macrophage chemotaxis. Sci. Signal. 3, ra55 (2010).
Chen, Y. et al. ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314, 1792–1795 (2006).
Zumerle, S. et al. Intercellular calcium signaling induced by ATP potentiates macrophage phagocytosis. Cell Rep. 27, 1–10.e14 (2019).
Feske, S., Wulff, H. & Skolnik, E. Y. Ion channels in innate and adaptive immunity. Annu. Rev. Immunol. 33, 291–353 (2015).
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).
Limagne, E. et al. Accumulation of MDSC and Th17 cells in patients with metastatic colorectal cancer predicts the efficacy of a FOLFOX–bevacizumab drug treatment regimen. Cancer Res. 76, 5241–5252 (2016).
Segovia, M. et al. Targeting TMEM176B enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation. Cancer Cell 35, 767–781.e6 (2019).
Reutershan, J. et al. Adenosine and inflammation: CD39 and CD73 are critical mediators in LPS-induced PMN trafficking into the lungs. FASEB J. 23, 473–482 (2009).
Kukulski, F. et al. NTPDase1 controls IL-8 production by human neutrophils. J. Immunol. 187, 644–653 (2011).
Di Virgilio, F., Dal Ben, D., Sarti, A. C., Giuliani, A. L. & Falzoni, S. The P2X7 receptor in infection and inflammation. Immunity 47, 15–31 (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).
Fang, F. et al. Expression of CD39 on activated T cells impairs their survival in older individuals. Cell Rep. 14, 1218–1231 (2016).
Ledderose, C. et al. Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration. J. Clin. Invest. 128, 3583–3594 (2018).
Plitas, G. & Rudensky, A. Y. Regulatory T cells: differentiation and function. Cancer Immunol. Res. 4, 721–725 (2016).
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). This important paper defines the role of CD39 on T reg cells in promoting tumour metastasis.
Ahlmanner, F. et al. CD39+ regulatory T cells accumulate in colon adenocarcinomas and display markers of increased suppressive function. Oncotarget 9, 36993–37007 (2018).
Retseck, J. et al. Long term impact of CTLA4 blockade immunotherapy on regulatory and effector immune responses in patients with melanoma. J. Transl. Med. 16, 184 (2018).
Peres, R. S. et al. TGF-β signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis. J. Autoimmun. 90, 49–58 (2018).
Gavin, M. A. et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445, 771–775 (2007).
De Marchi, E. et al. The P2X7 receptor modulates immune cells infiltration, ectonucleotidases expression and extracellular ATP levels in the tumor microenvironment. Oncogene 38, 3636–3650 (2019).
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).
Apetoh, L. et al. The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat. Immunol. 11, 854–861 (2010).
Gandhi, R. et al. Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3+ regulatory T cells. Nat. Immunol. 11, 846–853 (2010).
Bergmann, C., Strauss, L., Zeidler, R., Lang, S. & Whiteside, T. L. Expansion and characteristics of human T regulatory type 1 cells in co-cultures simulating tumor microenvironment. Cancer Immunol. Immunother. 56, 1429–1442 (2007).
Mandapathil, M. et al. CD26 expression and adenosine deaminase activity in regulatory T cells (Treg) and CD4+ T effector cells in patients with head and neck squamous cell carcinoma. Oncoimmunology 1, 659–669 (2012).
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).
Trimarchi, H. et al. Podocyturia: a clue for the rational use of amiloride in alport renal disease. Case Rep. Nephrol. 2016, 1492743 (2016).
Chalmin, F. et al. Stat3 and Gfi-1 transcription factors control TH17 cell immunosuppressive activity via the regulation of ectonucleotidase expression. Immunity 36, 362–373 (2012).
Simoni, Y. et al. Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 557, 575–579 (2018). This paper demonstrates that not all tumour-infiltrating T cells are specific for tumour antigens and suggests that measuring CD39 expression might be a simple way to quantify bystander T cells.
Canale, F. P. et al. CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells. Cancer Res. 78, 115–128 (2018).
Duhen, T. et al. Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat. Commun. 9, 2724 (2018).
Thelen, M., Lechner, A., Wennhold, K., von Bergwelt-Baildon, M. & Schlosser, H. A. CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells — letter. Cancer Res. 78, 5173–5174 (2018).
Zhang, H. et al. The role of NK cells and CD39 in the immunological control of tumor metastases. Oncoimmunology 8, e1593809 (2019).
Yan, J. et al. Control of metastases via myeloid CD39 and NK cell effector function. Cancer Immunol. Res. 8, 356–367 (2020).
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).
Mascanfroni, I. D. et al. IL-27 acts on DCs to suppress the T cell response and autoimmunity by inducing expression of the immunoregulatory molecule CD39. Nat. Immunol. 14, 1054–1063 (2013).
Ma, Y. et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 38, 729–741 (2013).
Rao, S. et al. A dual role for autophagy in a murine model of lung cancer. Nat. Commun. 5, 3056 (2014).
Schnurr, M. et al. Extracellular ATP and TNF-α synergize in the activation and maturation of human dendritic cells. J. Immunol. 165, 4704–4709 (2000).
Wilkin, F. et al. The P2Y11 receptor mediates the ATP-induced maturation of human monocyte-derived dendritic cells. J. Immunol. 166, 7172–7177 (2001).
Yoshida, O. et al. CD39 expression by hepatic myeloid dendritic cells attenuates inflammation in liver transplant ischemia–reperfusion injury in mice. Hepatology 58, 2163–2175 (2013).
la Sala, A. et al. Extracellular ATP induces a distorted maturation of dendritic cells and inhibits their capacity to initiate TH1 responses. J. Immunol. 166, 1611–1617 (2001).
Feng, L. et al. Vascular CD39/ENTPD1 directly promotes tumor cell growth by scavenging extracellular adenosine triphosphate. Neoplasia 13, 206–216 (2011).
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). This study generates two antibodies, IPH5201 and IPH5301, targeting human membrane-associated and soluble forms of CD39 and CD73, respectively. The results support the use of these mAbs and their combination with immune checkpoint inhibitors and chemotherapies in cancer.
Sun, X. et al. Disordered purinergic signaling and abnormal cellular metabolism are associated with development of liver cancer in Cd39/ENTPD1 null mice. Hepatology 57, 205–216 (2013).
Kunzli, B. M. et al. Impact of CD39 and purinergic signalling on the growth and metastasis of colorectal cancer. Purinergic Signal. 7, 231–241 (2011).
Schaefer, U., Machida, T., Broekman, M. J., Marcus, A. J. & Levi, R. Targeted deletion of ectonucleoside triphosphate diphosphohydrolase 1/CD39 leads to desensitization of pre- and postsynaptic purinergic P2 receptors. J. Pharmacol. Exp. Ther. 322, 1269–1277 (2007).
Vigano, S. et al. Targeting adenosine in cancer immunotherapy to enhance T-cell function. Front. Immunol. 10, 925 (2019).
Montalban Del Barrio, I. et al. Adenosine-generating ovarian cancer cells attract myeloid cells which differentiate into adenosine-generating tumor associated macrophages — a self-amplifying, CD39- and CD73-dependent mechanism for tumor immune escape. J. Immunother. Cancer 4, 49 (2016).
Kuhny, M., Hochdorfer, T., Ayata, C., Idzko, M. & Huber, M. CD39 is a negative regulator of P2X7-mediated inflammatory cell death in mast cells. Cell Commun. Signal. 12, 40 (2014).
Schenk, U. et al. ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors. Sci. Signal. 4, ra12 (2011).
Kashyap, A. S. et al. Antisense oligonucleotide targeting CD39 improves anti-tumor T cell immunity. J. Immunother. Cancer 7, 67 (2019).
Roberts, E. W. et al. Critical role for CD103+/CD141+ dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell 30, 324–336 (2016).
Novitskiy, S. V. et al. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 112, 1822–1831 (2008).
Panther, E. et al. Adenosine affects expression of membrane molecules, cytokine and chemokine release, and the T-cell stimulatory capacity of human dendritic cells. Blood 101, 3985–3990 (2003).
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).
Wilson, J. M. et al. The A2B adenosine receptor impairs the maturation and immunogenicity of dendritic cells. J. Immunol. 182, 4616–4623 (2009).
Ben Addi, A. et al. Modulation of murine dendritic cell function by adenine nucleotides and adenosine: involvement of the A(2B) receptor. Eur. J. Immunol. 38, 1610–1620 (2008).
Warren, M. et al. The fully human antibody SRF617 is a potent enzymatic inhibitor of CD39 with strong immunomodulatory activity (Poster 652). J. Immunother. Cancer 7 (Suppl. 2), 283 (2019).
Qiu, Y. et al. The anti-tumor activity of an anti-CD39 antibody (ES002) in a multiple myeloma model is dependent on NK cells (Poster 790). J. Immunother. Cancer 7 (Suppl. 2), 283 (2019).
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).
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. N. Drugs 37, 711–721 (2019).
Enjyoji, K. et al. Deletion of CD39/ENTPD1 results in hepatic insulin resistance. Diabetes 57, 2311–2320 (2008).
Lanser, A. J. et al. Disruption of the ATP/adenosine balance in CD39–/– mice is associated with handling-induced seizures. Immunology 152, 589–601 (2017).
Nardi-Schreiber, A. et al. Defective ATP breakdown activity related to an ENTPD1 gene mutation demonstrated using 31P NMR spectroscopy. Chem. Commun. 53, 9121–9124 (2017).
Overman, M. J. et al. Safety, efficacy and pharmacodynamics (PD) of MEDI9447 (oleclumab) alone or in combination with durvalumab in advanced colorectal cancer or pancreatic cancer [abstract]. J. Clin. Oncol. 36 (Suppl), 4123 (2018).
Chiappori, A. et al. Phase I/II study of the A2AR antagonist NIR178 (PBF-509), an oral immunotherapy, in patients (pts) with advanced NSCLC [abstract]. J. Clin. Oncol. 36 (Suppl), 9089 (2018).
Fong, L. et al. Adenosine 2A receptor blockade as an immunotherapy for treatment-refractory renal cell cancer. Cancer Discov. 10, 40–53 (2020). This first-in-human study of an A 2A antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumour activity with single-agent and anti-PDL1 combination therapy in patients with refractory RCC.
Tang, J., Shalabi, A. & Hubbard-Lucey, V. M. Comprehensive analysis of the clinical immuno-oncology landscape. Ann. Oncol. 29, 84–91 (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).
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).
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).
Gupta, P. K. et al. CD39 expression identifies terminally exhausted CD8+ T cells. PLoS Pathog. 11, e1005177 (2015).
Giannakis, M. et al. Metabolomic correlates of response in nivolumab-treated renal cell carcinoma and melanoma patients [abstract]. J. Clin. Oncol. 35 (Suppl. 15), 3036 (2017).
Boyd-Tressler, A., Penuela, S., Laird, D. W. & Dubyak, G. R. Chemotherapeutic drugs induce ATP release via caspase-gated pannexin-1 channels and a caspase/pannexin-1-independent mechanism. J. Biol. Chem. 289, 27246–27263 (2014).
Aroua, N. et al. Extracellular ATP and CD39 activate cAMP-mediated mitochondrial stress response to promote cytarabine resistance in acute myeloid leukemia. Preprint at bioRxiv https://doi.org/10.1101/806992 (2020).
Sheth, S. et al. Heightened NTPDase-1/CD39 expression and angiogenesis in radiation proctitis. Purinergic Signal. 5, 321–326 (2009).
Michaud, M. et al. Subversion of the chemotherapy-induced anticancer immune response by the ecto-ATPase CD39. Oncoimmunology 1, CD393–CD395 (2012).
Sade-Feldman, M. et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 175, 998–1013.e20 (2018).
Sitkovsky, M. V. Lessons from the A2A adenosine receptor antagonist-enabled tumor regression and survival in patients with treatment-refractory renal cell cancer. Cancer Discov. 10, 16–19 (2020).
Beavis, P. A. et al. Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy. J. Clin. Invest. 127, 929–941 (2017).
Mittal, D. et al. Adenosine 2B receptor expression on cancer cells promotes metastasis. Cancer Res. 76, 4372–4382 (2016).
Di Virgilio, F. & Adinolfi, E. Extracellular purines, purinergic receptors and tumor growth. Oncogene 36, 293–303 (2017).
Houthuys, E. et al. A novel non-competitive and non-brain penetrant adenosine A2A receptor antagonist designed to reverse adenosine-mediated suppression of anti-tumor immunity. J. Immunother. Cancer 5 (Suppl. 2), 87 (2017).
Ferrari, D. et al. Extracellular ATP triggers IL-1β release by activating the purinergic P2Z receptor of human macrophages. J. Immunol. 159, 1451–1458 (1997).
Gaidt, M. M. & Hornung, V. The NLRP3 inflammasome renders cell death pro-inflammatory. J. Mol. Biol. 430, 133–141 (2018).
Fuller, S. J., Stokes, L., Skarratt, K. K., Gu, B. J. & Wiley, J. S. Genetics of the P2X7 receptor and human disease. Purinergic Signal. 5, 257–262 (2009).
Gu, B. J. et al. A Glu-496 to Ala polymorphism leads to loss of function of the human P2X7 receptor. J. Biol. Chem. 276, 11135–11142 (2001).
Cabrini, G. et al. A His-155 to Tyr polymorphism confers gain-of-function to the human P2X7 receptor of human leukemic lymphocytes. J. Immunol. 175, 82–89 (2005).
Sun, C., Chu, J., Singh, S. & Salter, R. D. Identification and characterization of a novel variant of the human P2X(7) receptor resulting in gain of function. Purinergic Signal. 6, 31–45 (2010).
Stokes, L. et al. Two haplotypes of the P2X(7) receptor containing the Ala-348 to Thr polymorphism exhibit a gain-of-function effect and enhanced interleukin-1β secretion. FASEB J. 24, 2916–2927 (2010).
Taylor, S. R. et al. Sequential shrinkage and swelling underlie P2X7-stimulated lymphocyte phosphatidylserine exposure and death. J. Immunol. 180, 300–308 (2008).
Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671 (2015).
Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665 (2015).
Kayagaki, N. et al. Non-canonical inflammasome activation targets caspase-11. Nature 479, 117–121 (2011).
Carty, M. et al. Cell survival and cytokine release after inflammasome activation is regulated by the Toll-IL-1R protein SARM. Immunity 50, 1412–1424.e6 (2019).
Heinrich, D., Bruland, O., Guise, T. A., Suzuki, H. & Sartor, O. Alkaline phosphatase in metastatic castration-resistant prostate cancer: reassessment of an older biomarker. Future Oncol. 14, 2543–2556 (2018).
Kunzli, B. et al. Disordered pancreatic inflammatory responses and inhibition of fibrosis in CD39-null mice. Gastroenterology 134, 292–305 (2008).
Fernandez, P. et al. Extracellular generation of adenosine by the ectonucleotidases CD39 and CD73 promotes dermal fibrosis. Am. J. Pathol. 183, 1740–1746 (2013).
Fernandez, P. et al. Pharmacological blockade of A2A receptors prevents dermal fibrosis in a model of elevated tissue adenosine. Am. J. Pathol. 172, 1675–1682 (2008).
Dranoff, J. et al. Expression of P2Y nucleotide receptors and ectonucleotidases in quiescent and activated rat hepatic stellate cells. Am. J. Physiol. Gastrointest. Liver Physiol. 287, G417–G424 (2004).
Goncalves, R. G. et al. The role of purinergic P2X7 receptors in the inflammation and fibrosis of unilateral ureteral obstruction in mice. Kidney Int. 70, 1599–1606 (2006).
Lu, D., Soleymani, S., Madakshire, R. & Insel, P. A. ATP released from cardiac fibroblasts via connexin hemichannels activates profibrotic P2Y2 receptors. FASEB J. 26, 2580–2591 (2012).
Riteau, N. et al. Extracellular ATP is a danger signal activating P2X7 receptor in lung inflammation and fibrosis. Am. J. Respir. Crit. Care Med. 182, 774–783 (2010).
Allard, B. et al. Anti-CD73 therapy impairs tumor angiogenesis. Int. J. Cancer 134, 1466–1473 (2014).
Salimu, J. et al. Dominant immunosuppression of dendritic cell function by prostate-cancer-derived exosomes. J. Extracell. Vesicles 6, 1368823 (2017).
Morandi, F. et al. Microvesicles released from multiple myeloma cells are equipped with ectoenzymes belonging to canonical and non-canonical adenosinergic pathways and produce adenosine from ATP and NAD. Oncoimmunology 7, e1458809 (2018).
Theodoraki, M. N., Hoffmann, T. K., Jackson, E. K. & Whiteside, T. L. Exosomes in HNSCC plasma as surrogate markers of tumour progression and immune competence. Clin. Exp. Immunol. 194, 67–78 (2018).
Morandi, F., Marimpietri, D., Horenstein, A. L., Corrias, M. V. & Malavasi, F. Microvesicles expressing adenosinergic ectoenzymes and their potential role in modulating bone marrow infiltration by neuroblastoma cells. Oncoimmunology 8, e1574198 (2019).
Muller, L., Mitsuhashi, M., Simms, P., Gooding, W. E. & Whiteside, T. L. Tumor-derived exosomes regulate expression of immune function-related genes in human T cell subsets. Sci. Rep. 6, 20254 (2016).
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).
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).
The authors thank members of their laboratories and H. Deng (The Fourth Affiliated Hospital of Nanchang University) for figure preparation. M.J.S. was supported by a National Health and Medical Research Council (NH&MRC) Investigator Fellowship (1173958) and Program Grant (1132519) and a Melanoma Research Alliance Established Investigator Award (611295).
M.J.S. has research agreements with Bristol Myers Squibb and Tizona Therapeutics, and is on the Scientific Advisory Board of Tizona Therapeutics and Compass Therapeutics. A.K.M. is an employee of Tizona Therapeutics.
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Moesta, A.K., Li, X. & Smyth, M.J. Targeting CD39 in cancer. Nat Rev Immunol (2020). https://doi.org/10.1038/s41577-020-0376-4