Abstract
Cancer immunotherapy has entered in a new era with the development of first-generation immune checkpoint inhibitors targeting the PD1/PD-L1 and CTLA-4 pathways. In this context, considerable research effort is being deployed to find the next generation of cancer immunotherapeutics. The CD73–adenosine axis constitutes one of the most promising pathways in immuno-oncology. We and others have demonstrated the immunosuppressive role of CD73–adenosine in cancer and established proof-of-concept that the targeted blockade of CD73 or adenosine receptors could effectively promote anti-tumor immunity and enhance the activity of first-generation immune checkpoint blockers. With Phase I clinical trials now underway evaluating anti-CD73 or anti-A2A therapies in cancer patients, we here discuss the fundamental, preclinical and clinical findings related to the role of the CD73–adenosinergic pathway in tumor immunity.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 Cell stress increases ATP release in NLRP3 inflammasome-mediated autoinflammatory diseases, resulting in cytokine imbalance. Proc. Natl Acad. Sci. USA 112(9), 2835–2840 (2015).
- 2 Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461(7261), 282–286 (2009).
- 3 . The P2X7 receptor is a key modulator of aerobic glycolysis. Cell Death Dis. 3, e370 (2012).
- 4 . Immunity, inflammation and cancer: a leading role for adenosine. Nat. Rev. Cancer 13(12), 842–857 (2013).
- 5 . CD39 and CD73 in immunity and inflammation. Trends Mol. Med. 19(6), 355–367 (2013).
- 6 . Targeting CD73 and downstream adenosine receptor signaling in triple-negative breast cancer. Expert Opin. Ther. Targets 18(8), 863–881 (2014).
- 7 Early prediction of persistent organ failure by soluble CD73 in patients with acute pancreatitis*. Crit. Care Med. 42(12), 2556–2564 (2014).
- 8 . IFN-beta regulates CD73 and adenosine expression at the blood–brain barrier. Eur. J. Immunol. 38(10), 2718–2726 (2008).
- 9 . Characterization of different molecular forms of 5′-nucleotidase in normal serum and in serum from cholestatic patients and bile-duct-ligated rats. Biochem. J. 224(3), 689–695 (1984).
- 10 High expression and activity of ecto-5′-nucleotidase/CD73 in the male murine reproductive tract. Histochem. Cell Biol. 133(6), 659–668 (2010).
- 11 Biochemical and mass spectrometric characterization of soluble ecto-5′-nucleotidase from bull seminal plasma. Biochem. J. 372(Pt 2), 443–451 (2003).
- 12 . 5′-nucleotidase as a marker of both general and local inflammation in rheumatoid arthritis patients. Rheumatology (Oxford) 38(5), 391–396 (1999).
- 13 . Oncogenic G protein GNAQ induces uveal melanoma and intravasation in mice. Cancer Res. 75(16), 3384–3397 (2015).
- 14 Autoimmunity in CD73/Ecto-5′-nucleotidase deficient mice induces renal injury. PLoS ONE 7(5), e37100 (2012).
- 15 Impairment of tubuloglomerular feedback regulation of GFR in ecto-5′-nucleotidase/CD73-deficient mice. J. Clin. Invest. 114(5), 634–642 (2004).
- 16 Targeted disruption of cd73/ecto-5′-nucleotidase alters thromboregulation and augments vascular inflammatory response. Circ. Res. 95(8), 814–821 (2004).
- 17 . Neutrophil-derived 5′-adenosine monophosphate promotes endothelial barrier function via CD73-mediated conversion to adenosine and endothelial A2B receptor activation. J. Exp. Med. 188(8), 1433–1443 (1998).
- 18 Crucial role for ecto-5′-nucleotidase (CD73) in vascular leakage during hypoxia. J. Exp. Med. 200(11), 1395–1405 (2004).
- 19 Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J. Clin. Invest. 110(7), 993–1002 (2002).
- 20 Different role of CD73 in leukocyte trafficking via blood and lymph vessels. Blood 117(16), 4387–4393 (2011).
- 21 CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 105(27), 9325–9330 (2008).
- 22 Protective role of ecto-5′-nucleotidase (CD73) in renal ischemia. J. Am. Soc. Nephrol. 18(3), 833–845 (2007).
- 23 Cardioprotection by ecto-5′-nucleotidase (CD73) and A2B adenosine receptors. Circulation 115(12), 1581–1590 (2007).
- 24 Ecto-5′-nucleotidase (CD73) -mediated extracellular adenosine production plays a critical role in hepatic fibrosis. FASEB J. 22(7), 2263–2272 (2008).
- 25 . Transfer of the glycosylphosphatidylinositol-anchored 5′-nucleotidase CD73 from adiposomes into rat adipocytes stimulates lipid synthesis. Br. J. Pharmacol. 160(4), 878–891 (2010).
- 26 . Adenosine receptor signaling in the brain immune system. Trends Pharmacol. Sci. 26(10), 511–516 (2005).
- 27 Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204(6), 1257–1265 (2007). •• First report showing that adenosine produced by the sequential action of CD39 and CD73 is major immunosuppressive mechanism used by Tregs.
- 28 CD73-deficient mice have increased anti-tumor immunity and are resistant to experimental metastasis. Cancer Res. 71(8), 2892–2900 (2011). •• First report showing that host CD73 is involved in anti-tumor immunity.
- 29 NT5E mutations and arterial calcifications. N. Engl. J. Med. 364(5), 432–442 (2011).
- 30 . NT5E mutations that cause human disease are associated with intracellular mistrafficking of NT5E protein. PLoS ONE 9(6), e98568 (2014).
- 31 . Juxta-articular joint-capsule mineralization in CD73 deficient mice: similarities to patients with NT5E mutations. Cell cycle (Georgetown, TX) 13(16), 2609–2615 (2014).
- 32 . 2-Chloroadenosine inhibits the MHC-unrestricted cytolytic activity of anti-CD3-activated killer cells: evidence for the involvement of a non-A1/A2 cell-surface adenosine receptor. Cell. Immunol. 159(1), 85–93 (1994).
- 33 . Adenosine as a possible inhibitor of killer T-cell activation in the microenvironment of solid tumours. Int. J. Cancer 59(6), 854–855 (1994).
- 34 . Adenosine inhibits the adhesion of anti-CD3-activated killer lymphocytes to adenocarcinoma cells through an A3 receptor. Cancer Res. 54(13), 3521–3526 (1994).
- 35 . Adenosine acts through a novel extracellular receptor to inhibit granule exocytosis by natural killer cells. Biochem. Biophys. Res. Commun. 231(2), 264–269 (1997).
- 36 . The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res. 57(13), 2602–2605 (1997). • First report showing that adenosine levels are elevated in the tumor microenvironment and capable of mediating immunosuppression.
- 37 . Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood 90(4), 1600–1610 (1997).
- 38 . Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414(6866), 916–920 (2001). •• First report showing the importance of A2A activation for the protection of tissues against against inflammatory reactions.
- 39 A2A adenosine receptor protects tumors from anti-tumor T cells. Proc. Natl Acad. Sci. USA 103(35), 13132–13137 (2006). •• First report showing that a deficiency in host A2A receptors confers resitance to tumor growth in mice.
- 40 . CD73: a novel target for cancer immunotherapy. Cancer Res. 70(16), 6407–6411 (2010).
- 41 CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. J. Clin. Invest. 121(6), 2371–2382 (2011).
- 42 Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc. Natl Acad. Sci. USA 107(4), 1547–1552 (2010). •• First report demonstrating that the targeted blockade of CD73 can reduce tumor growth and metastasis through the activation of anti-tumor immunity.
- 43 . Targeting CD73 enhances the anti-tumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin. Cancer Res. 19(20), 5626–5635 (2013).
- 44 Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proc. Natl Acad. Sci. USA 110(36), 14711–14716 (2013).
- 45 Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer Res. 74(14), 3652–3658 (2014).
- 46 . Transcriptional control of adenosine signaling by hypoxia-inducible transcription factors during ischemic or inflammatory disease. J. Mol. Med. (Berl.) 91(2), 183–193 (2013).
- 47 Hostile, hypoxia-A2-adenosinergic tumor biology as the next barrier to overcome for tumor immunologists. Cancer Immunol. Res. 2(7), 598–605 (2014).
- 48 CD73 is associated with poor prognosis in high-grade serous ovarian cancer. Cancer Res. 75(21), 4494–4503 (2015). •• First report showing that CD73 expression correlates with poor prognosis in tha major subtype of ovarian cancer.
- 49 CD73 expression is an independent prognostic factor in prostate cancer. Clin. Cancer. Res.
doi:10.1158/1078-0432.CCR-15-1181 (2015) (Epub ahead of print). - 50 CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer. Proc. Natl Acad. Sci. USA 110(27), 11091–11096 (2013). •• First clinical evidence that CD73 correlates with prognosis and response to therapy in triple-negative breast cancers.
- 51 IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients. J. Clin. Invest. 124(1), 99–110 (2014).
- 52 Reducing CD73 expression by IL1beta-programmed Th17 cells improves immunotherapeutic control of tumors. Cancer Res. 74(21), 6048–6059 (2014).
- 53 Adenosine and prostaglandin E2 cooperate in the suppression of immune responses mediated by adaptive regulatory T cells. J. Biol. Chem. 285(36), 27571–27580 (2010).
- 54 The effect of intravenous interferon-beta-1a (FP-1201) on lung CD73 expression and on acute respiratory distress syndrome mortality: an open-label study. Lancet Respir. Med. 2(2), 98–107 (2014).
- 55 . Dual, enzymatic and non-enzymatic, function of ecto-5′-nucleotidase (eN, CD73) in migration and invasion of A375 melanoma cells. Acta Biochim. Pol. 59(4), 647–652 (2012).
- 56 Anti-CD73 therapy impairs tumor angiogenesis. Int. J. Cancer 134(6), 1466–1473 (2014).
- 57 . p73 engages A2B receptor signalling to prime cancer cells to chemotherapy-induced death. Oncogene 34(40), 5152–5162 (2015).
- 58 . Adenosine-induced apoptosis in EL-4 thymoma cells is caspase-independent and mediated through a non-classical adenosine receptor. Exp. Mol. Pathol. 79(3), 249–258 (2005).
- 59 . A new, sensitive ecto-5′-nucleotidase assay for compound screening. Anal. Biochem. 446, 53–58 (2014).
- 60 . Pattern of metastatic spread in triple-negative breast cancer. Breast Cancer Res. Treat. 115(2), 423–428 (2009).
- 61 Prognosis and adjuvant treatment effects in selected breast cancer subtypes of very young women (<35 years) with operable breast cancer. Ann. Oncol. 21(10), 1974–1981 (2010).
- 62 Ecto-5′-nucleotidase promotes invasion, migration and adhesion of human breast cancer cells. J. Cancer Res. Clin. Oncol. 134(3), 365–372 (2008).
- 63 Antagonism of adenosine A2A receptor expressed by lung adenocarcinoma tumor cells and cancer associated fibroblasts inhibits their growth. Cancer Biol. Ther. 14(9), 860–868 (2013).
- 64 . Extracellular adenosine regulates naive T cell development and peripheral maintenance. J. Exp. Med. 210(12), 2693–2706 (2013).
- 65 . Virtual screening identifies novel sulfonamide inhibitors of ecto-5′-nucleotidase. J. Med. Chem. 55(14), 6576–6581 (2012).
- 66 . Overexpression of CD73 in epithelial ovarian carcinoma is associated with better prognosis, lower stage, better differentiation and lower regulatory T cell infiltration. J. Gynecol. Oncol. 23(4), 274–281 (2012).
- 67 Alpha, beta-methylene-ADP (AOPCP) derivatives and analogues: development of potent and selective ecto-5′-nucleotidase (CD73) inhibitors. J. Med. Chem. 58(15), 6248–6263 (2015).
- 68 Development of potent and selective inhibitors of ecto-5′-nucleotidase based on an anthraquinone scaffold. J. Med. Chem. 53(5), 2076–2086 (2010).
- 69 Identification of sulfonic acids as efficient ecto-5′-nucleotidase inhibitors. Eur. J. Med. Chem. 70, 685–691 (2013).
- 70 . Ecto-5′-nucleotidase/CD73 inhibition by quercetin in the human U138MG glioma cell line. Biochim. Biophys. Acta 1770(9), 1352–1359 (2007).
- 71 Production and characterization of monoclonal antibodies to the glycosyl phosphatidylinositol-anchored lymphocyte differentiation antigen ecto-5′-nucleotidase (CD73). Tissue Antigens 35(1), 9–19 (1990).
- 72 . Immunotherapeutic approaches in triple-negative breast cancer: latest research and clinical prospects. Ther. Adv. Med. Oncol. 5(3), 169–181 (2013).
- 73 Triple-negative breast cancer: clinical features and patterns of recurrence. Clin. Cancer. Res. 13(15 Pt 1), 4429–4434 (2007).
- 74 . Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry. Cancer 109(9), 1721–1728 (2007).
- 75 The prognostic contribution of clinical breast cancer subtype, age, and race among patients with breast cancer brain metastases. Cancer 117(8), 1602–1611 (2011).
- 76 Molecular portraits of human breast tumours. Nature 406(6797), 747–752 (2000).
- 77 Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin. Cancer Res. 10(16), 5367–5374 (2004).
- 78 Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295(21), 2492–2502 (2006).
- 79 Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J. Clin. Oncol. 26(8), 1275–1281 (2008).
- 80 Therapeutic targets in triple negative breast cancer. J. Clin. Pathol. 66(6), 530–542 (2013).
- 81 Combining phenotypic and proteomic approaches to identify membrane targets in a ‘triple negative’ breast cancer cell type. Mol. Cancer 12, 11 (2013).
- 82 Anti-human CD73 monoclonal antibody inhibits metastasis formation in human breast cancer by inducing clustering and internalization of CD73 expressed on the surface of cancer cells. J. Immunol. 191(8), 4165–4173 (2013).
- 83 . Role of estrogen receptor in the regulation of ecto-5′-nucleotidase and adenosine in breast cancer. Clin. Cancer Res. 10(2), 708–717 (2004).
- 84 RNA interference of ecto-5′-nucleotidase (CD73) inhibits human breast cancer cell growth and invasion. Clin. Exp. Metastasis 24(6), 439–448 (2007).
- 85 RNAi-mediated CD73 suppression induces apoptosis and cell-cycle arrest in human breast cancer cells. Cancer Sci. 101(12), 2561–2569 (2010).
- 86 Effects of ecto-5′-nucleotidase on human breast cancer cell growth in vitro and in vivo. Oncol. Rep. 17(6), 1341–1346 (2007).
- 87 Differential impact of adenosine nucleotides released by osteocytes on breast cancer growth and bone metastasis. Oncogene 34(14), 1831–1842 (2015).
- 88 Adenosine inhibits tumor cell invasion via receptor-independent mechanisms. Mol. Cancer Res. 12(12), 1863–1874 (2014).
- 89 Ecto-5′-nucleotidase (CD73) promotes tumor angiogenesis. Clin. Exp. Metastasis 30(5), 671–680 (2013).
- 90 Identification of a pharmacologically tractable Fra-1/ADORA2B axis promoting breast cancer metastasis. Proc. Natl. Acad. Sci. USA 110(13), 5139–5144 (2013).
- 91 . Adenosine A2B receptor blockade slows growth of bladder and breast tumors. J. Immunol. 188(1), 198–205 (2012).
- 92 An adenosine-mediated signaling pathway suppresses prenylation of the GTPase Rap1B and promotes cell scattering. Sci. Signal. 6(277), ra39 (2013).
- 93 New markers for minimal residual disease detection in acute lymphoblastic leukemia. Blood 117(23), 6267–6276 (2011).
- 94 CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death. Blood 118(23), 6141–6152 (2011).
- 95 . Prognostic markers and their clinical applicability in chronic lymphocytic leukemia: where do we stand? Leuk. Lymphoma 54(11), 2351–2364 (2013).
- 96 Regulatory T-cells in B-cell chronic lymphocytic leukemia: their role in disease progression and autoimmune cytopenias. Leuk. Lymphoma 54(5), 1012–1019 (2013).
- 97 . Ectonucleoside triphosphate diphosphohydrolase-1 (E-NTPDase1/CD39) as a new prognostic marker in chronic lymphocytic leukemia. Leuk. Lymphoma 56(1), 113–119 (2015).
- 98 The role of ecto-5′-nucleotidase/CD73 in glioma cell line proliferation. Mol. Cell. Biochem. 319(1–2), 61–68 (2008).
- 99 Synergy between the ectoenzymes CD39 and CD73 contributes to adenosinergic immunosuppression in human malignant gliomas. Neuro Oncol. 15(9), 1160–1172 (2013).
- 100 5′-ectonucleotidase mediates multiple-drug resistance in glioblastoma multiforme cells. J. Cell. Physiol. 228(3), 602–608 (2013).
- 101 Primary glioblastomas express mesenchymal stem-like properties. Mol. Cancer Res. 4(9), 607–619 (2006).
- 102 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).
- 103 . Modulation of A1 and A2B adenosine receptor activity: a new strategy to sensitise glioblastoma stem cells to chemotherapy. Cell Death Dis. 5, e1539 (2014).
- 104 A1 adenosine receptors in microglia control glioblastoma-host interaction. Cancer Res. 66(17), 8550–8557 (2006).
- 105 . Adenosine receptor signaling: a key to opening the blood–brain door. Fluids Barriers CNS 12(1), 20 (2015).
- 106 . Adenosine receptor signaling modulates permeability of the blood–brain barrier. J. Neurosci. 31(37), 13272–13280 (2011).
- 107 Chronic caffeine treatment attenuates experimental autoimmune encephalomyelitis induced by guinea pig spinal cord homogenates in Wistar rats. Brain Res. 1309, 116–125 (2010).
- 108 A1 adenosine receptor upregulation and activation attenuates neuroinflammation and demyelination in a model of multiple sclerosis. J. Neurosci. 24(6), 1521–1529 (2004).
- 109 . Extracellular adenosine signaling induces CX3CL1 expression in the brain to promote experimental autoimmune encephalomyelitis. J. Neuroinflammation 9, 193 (2012).
- 110 Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus. Immunity 38(3), 555–569 (2013).
- 111 Human brain endothelial cells are responsive to adenosine receptor activation. Purinergic Signal. 7(2), 265–273 (2011).
- 112 . A2A adenosine receptor regulates the human blood–brain barrier permeability. Mol. Neurobiol. 52(1), 664–678 (2015).
- 113 Tissue-resident ecto-5′ nucleotidase (CD73) regulates leukocyte trafficking in the ischemic brain. J. Immunol. 188(5), 2387–2398 (2012).
- 114 Genetic inactivation of the adenosine A(2A) receptor exacerbates brain damage in mice with experimental autoimmune encephalomyelitis. J. Neurochem. 123(1), 100–112 (2012).
- 115 Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc. Natl Acad. Sci. USA 108(17), 7142–7147 (2011).
- 116 CD73-deficient mice are resistant to carcinogenesis. Cancer Res. 72(9), 2190–2196 (2012).
- 117 . Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironment. Cancer Res. 74(24), 7250–7259 (2014).
- 118 Immunological mechanisms of the anti-tumor effects of supplemental oxygenation. Sci. Transl. Med. 7(277), 277ra230 (2015).
- 119 Host A(2B) adenosine receptors promote carcinoma growth. Neoplasia 10(9), 987–995 (2008).
- 120 Knockdown of oncogenic KRAS in non-small cell lung cancers suppresses tumor growth and sensitizes tumor cells to targeted therapy. Mol. Cancer Ther. 10(2), 336–346 (2011).
- 121 KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 66(8), 3992–3995 (2006).
- 122 . EGFR gene copy number assessment from areas with highest EGFR expression predicts response to anti-EGFR therapy in colorectal cancer. Br. J. Cancer 105(2), 255–262 (2011).
- 123 Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J. Clin. Oncol. 25(22), 3230–3237 (2007).
- 124 . Autophagy in non-small cell lung carcinogenesis: a positive regulator of anti-tumor immunosurveillance. Autophagy 10(3), 529–531 (2014).
- 125 . Expression of ecto-5′-nucleotidase (eN, CD73) in cell lines from various stages of human melanoma. Melanoma Res. 16(3), 213–222 (2006).
- 126 . Ecto-5′-nucleotidase (eN, CD73) is coexpressed with metastasis promoting antigens in human melanoma cells. Nucleosides Nucleotides Nucleic Acids 25(9–11), 1119–1123 (2006).
- 127 NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity. Br. J. Cancer 106(8), 1446–1452 (2012).
- 128 Altered purinergic signaling in CD73-deficient mice inhibits tumor progression. Eur. J. Immunol. 41(5), 1231–1241 (2011).
- 129 Growth and metastasis of B16-F10 melanoma cells is not critically dependent on host CD73 expression in mice. BMC Cancer 14, 898 (2014).
- 130 . Adenosine limits the therapeutic effectiveness of anti-CTLA4 mAb in a mouse melanoma model. Am. J. Cancer Res. 4(2), 172–181 (2014).
- 131 Inhibition of CD73 stimulates the migration and invasion of B16F10 melanoma cells in vitro but results in impaired angiogenesis and reduced melanoma growth in vivo. Oncol. Rep. 31(2), 819–827 (2014).
- 132 . Enhancement of tumor immunotherapy by deletion of the A2A adenosine receptor. Cancer Immunol. Immunother. 61(6), 917–926 (2012).
- 133 Inhibition of CD73 improves B cell-mediated anti-tumor immunity in a mouse model of melanoma. J. Immunol. 189(5), 2226–2233 (2012).
- 134 . Adenosine A(2B) receptor antagonist PSB603 suppresses tumor growth and metastasis by inhibiting induction of regulatory T cells. J. Toxicol. Sci. 39(2), 191–198 (2014).
- 135 . 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(12), 1400–1409 (2013).
- 136 . Cancer statistics, 2009. CA Cancer J. Clin. 59(4), 225–249 (2009).
- 137 Safety and anti-tumor activity of anti-PD-1 antibody, Nivolumab, in patients with platinum-resistant ovarian cancer. J. Clin. Oncol. 33(34), 4015–4022 (2015).
- 138 . Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 73(12), 3591–3603 (2013).
- 139 . Indoleamine 2,3-dioxygenase is a critical resistance mechanism in anti-tumor T cell immunotherapy targeting CTLA-4. J. Exp. Med. 210(7), 1389–1402 (2013).
- 140 CD73 on tumor cells impairs anti-tumor T-cell responses: a novel mechanism of tumor-induced immune suppression. Cancer Res. 70(6), 2245–2255 (2010).
- 141 Gene expression profile of ovarian serous papillary carcinomas: identification of metastasis-associated genes. Am. J. Obstet. Gynecol. 196(3), 245.e241–245.e211 (2007).
- 142 Impaired Th1 immunity in ovarian cancer patients is mediated by TNFR2+ Tregs within the tumor microenvironment. Clin. Immunol. 149(1), 97–110 (2013).
- 143 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(10), 1405–1418 (2011).
- 144 Anti-CD39 and anti-CD73 antibodies A1 and 7G2 improve targeted therapy in ovarian cancer by blocking adenosine-dependent immune evasion. Am. J. Transl. Res. 6(2), 129–139 (2014).
- 145 Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur. J. Cancer 49(6), 1374–1403 (2013).
- 146 Quality of life and satisfaction with outcome among prostate-cancer survivors. N. Engl. J. Med. 358(12), 1250–1261 (2008).
- 147 Integrated data from 2 randomized, double-blind, placebo-controlled, Phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 115(16), 3670–3679 (2009).
- 148 Overall survival analysis of a Phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J. Clin. Oncol. 28(7), 1099–1105 (2010).
- 149 Placebo-controlled Phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J. Clin. Oncol. 24(19), 3089–3094 (2006).
- 150 . Overexpression of CD73 in prostate cancer is associated with lymph node metastasis. Pathol. Oncol. Res. 19(4), 811–814 (2013).
- 151 . Expression of adenosine receptor subclasses in malignant and adjacent normal human prostate tissues. Prostate 75(7), 735–747 (2015).
- 152 . Extracellular adenosine induces apoptosis of human arterial smooth muscle cells via A(2b)-purinoceptor. Circ. Res. 86(1), 76–85 (2000).
- 153 . Activation of A2b adenosine receptor regulates ovarian cancer cell growth: involvement of Bax/Bcl-2 and caspase-3. Biochem. Cell Biol. 93(4), 321–329 (2015).
- 154 Extracellular adenosine sensing-a metabolic cell death priming mechanism downstream of p53. Mol. Cell 50(3), 394–406 (2013).
- 155 MEDI9447: enhancing anti-tumor immunity by targeting CD73 in the tumor microenviroment. Presented at: 106th Annual Meeting of the American Association for Cancer Research. Philadelphia, PA, USA, 18–22 April 2015.
- 156 Potential prognostic biomarker CD73 regulates epidermal growth factor receptor expression in human breast cancer. IUBMB Life 64(11), 911–920 (2012).
- 157 CD73 expression as a potential marker of good prognosis in breast carcinoma. Appl. Immunohistochem. Mol. Morphol. 20(2), 103–107 (2012).
- 158 NT5E CpG island methylation is a favourable breast cancer biomarker. Br. J. Cancer 107(1), 75–83 (2012).
- 159 . Overexpression of CD73 in prostate cancer is associated with lymph node metastasis. Pathol. Oncol. Res. 19(4), 811–814 (2013).
- 160 The expression and clinical significance of CD73 molecule in human rectal adenocarcinoma. Tumour Biol. 36(7), 5459–5466 (2015).
- 161 High expression of CD73 as a poor prognostic biomarker in human colorectal cancer. J. Surg. Oncol. 106(2), 130–137 (2012).
- 162 . 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(2), 365–374 (2014).
- 163 . Expression and clinical significance of CD73 and hypoxia-inducible factor-1alpha in gastric carcinoma. World J. Gastroenterol. 19(12), 1912–1918 (2013).
- 164 Ecto-5′-nucleotidase expression is associated with the progression of renal cell carcinoma. Oncol. Lett. 9(6), 2485–2494 (2015).
- 165 CD73 predicts favorable prognosis in patients with nonmuscle-invasive urothelial bladder cancer. Disease Marker 2015(1), 1–8 (2015).