Targeting immunosuppressive adenosine in cancer

Nature Reviews Cancer

Volumn 17, Issue 12, 2017, Pages 709-724

  Vijayan, Dipti ^a   Young, Arabella ^b   Teng, Michele W L ^a   Smyth, Mark J ^a  

^a QIMR BERGHOFER MEDICAL RESEARCH INSTITUTE   (Australia)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE RECEPTOR BLOCKING AGENT; ADENOSINE; ANTIBODY;

CANCER SURVIVAL; ENDOTHELIUM; EXOSOME; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; LYMPH NODE; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; REVIEW; SOLID MALIGNANT NEOPLASM; TUMOR GROWTH; ANIMAL; ANTAGONISTS AND INHIBITORS; CELLULAR IMMUNITY; DRUG EFFECTS; GENETICS; IMMUNOLOGY; METABOLISM; MOUSE; NEOPLASM; TUMOR MICROENVIRONMENT;

ADENOSINE; ANIMALS; ANTIBODIES; HUMANS; IMMUNITY, CELLULAR; METABOLIC NETWORKS AND PATHWAYS; MICE; NEOPLASMS; PURINERGIC P1 RECEPTOR ANTAGONISTS; TUMOR MICROENVIRONMENT;

EID: 85034829716     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc.2017.86     Document Type: Review

References (148)

1. Hatfield, S. M. et al. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci. Transl Med. 7, 277ra30 (2015).
2. 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).
3. Semenza, G. L. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J. Clin. Invest. 123, 3664-3671 (2013).
4. Thomlinson, R. H. & Gray, L. H. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br. J. Cancer. 9, 539-549 (1955).
5. Busse, M. & Vaupel, P. Accumulation of purine catabolites in solid tumors exposed to therapeutic hyperthermia. Experientia 52, 469-473 (1996).
6. 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).
7. Stagg, J. & Smyth, M. J. Extracellular adenosine triphosphate and adenosine in cancer. Oncogene 29, 5346-5358 (2010).
8. Ohta, A. A metabolic immune checkpoint: adenosine in tumor microenvironment. Front. Immunol. 7, 109 (2016).
9. 2A receptors as drug discovery target. J. Med. Chem. 57, 3623-3650 (2014).
10. 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).
11. Ohta, A. et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc. Natl Acad. Sci. USA 103, 13132-13137 (2006).
12. Vecchio, E. A. et al. Ligand-independent adenosine A2B receptor constitutive activity as a promoter of prostate cancer cell proliferation. J. Pharmacol. Exp. Ther. 357, 36-44 (2016).
13. Cronstein, B. N. et al. Neutrophil adherence to endothelium is enhanced via adenosine A1 receptors and inhibited via adenosine A2 receptors. J. Immunol. 148, 2201-2206 (1992).
14. Butler, M. et al. Impairment of adenosine A3 receptor activity disrupts neutrophil migratory capacity and impacts innate immune function in vivo. Eur. J. Immunol. 42, 3358-3368 (2012).
15. Allard, D., Allard, B., Gaudreau, P. O., Chrobak, P. & Stagg, J. CD73-adenosine: a next-generation target in immuno-oncology. Immunotherapy 8, 145-163 (2016).
16. 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).
17. Young, A., Mittal, D., Stagg, J. & Smyth, M. J. Targeting cancer-derived adenosine: new therapeutic approaches. Cancer Discov. 4, 879-888 (2014).
18. + tumors. Proc. Natl Acad. Sci. USA 110, 14711-14716 (2013).
19. 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).
20. Young, A. et al. Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor immune responses. Cancer Cell. 30, 391-403 (2016).
21. Mittal, D. et al. Adenosine 2B receptor expression on cancer cells promotes metastasis. Cancer Res. 76, 4372-4382 (2016).
22. 2B adenosine receptors promote carcinoma growth. Neoplasia 10, 987-995 (2008).
23. Stagg, J. et al. CD73-deficient mice have increased antitumor immunity and are resistant to experimental metastasis. Cancer Res. 71, 2892-2900 (2011).
24. 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).
25. + Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110, 1225-1232 (2007).
26. high human regulatory B cells (Breg). Oncoimmunology 5, e1082703 (2016).
27. + myeloid cells in tumors. J. Immunol. 193, 3155-3164 (2014).
28. 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).
29. + T cells. PLoS Pathog. 11, e1005177 (2015).
30. + regulatory T cells promotes hepatic metastatic tumor growth in mice. Gastroenterology 139, 1030-1040 (2010).
31. Jackson, S. W. et al. Disordered purinergic signaling inhibits pathological angiogenesis in Cd39/Entpd1-null mice. Am. J. Pathol. 171, 1395-1404 (2007).
32. Vijayan, D. et al. Selective activation of anti-CD73 mechanisms in control of primary tumors and metastases. Oncoimmunology 6, e1312044 (2017).
33. Stagg, J. et al. CD73-deficient mice are resistant to carcinogenesis. Cancer Res. 72, 2190-2196 (2012).
34. Beavis, P. A. et al. Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy. J. Clin. Invest. 127, 929-941 (2017).
35. Mittal, D. et al. Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer Res. 74, 3652-3658 (2014).
36. 2A adenosine receptor. Cancer Immunol. Immunother. 61, 917-926 (2012).
37. Ohta, A. & Sitkovsky, M. Extracellular adenosine-mediated modulation of regulatory T cells. Front. Immunol. 5, 304 (2014).
38. 2b 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).
39. 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).
40. Young, A. et al. Targeting adenosine in BRAF-mutant melanoma reduces tumor growth and metastasis. Cancer Res. 77, 4684-4696 (2017).
41. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02403193 (2016).
42. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02655822 (2017).
43. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02740985 (2017).
44. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02503774 (2017).
45. Biswas, S. K. Metabolic reprogramming of immune cells in cancer progression. Immunity 43, 435-449 (2015).
46. 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).
47. Tak, E. et al. Protective role of hypoxia-inducible factor-1 a-dependent CD39 and CD73 in fulminant acute liver failure. Toxicol. Appl. Pharmacol. 314, 72-81 (2017).
48. 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).
49. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646-674 (2011).
50. Klein, M. & Bopp, T Cyclic AMP represents a crucial component of Treg cell-mediated immune regulation. Front. Immunol. 7, 315 (2016).
51. Wang, P. et al. MicroRNA-128b suppresses tumor growth and promotes apoptosis by targeting A2bR in gastric cancer. Biochem. Biophys. Res. Commun. 467, 798-804 (2015).
52. 2A) expression: differential requirement for NF-KB binding to the proximal promoter. J. Immunol. 177, 7173-7183 (2006).
53. Inoue, Y. et al. Prognostic impact of CD73 and A2A adenosine receptor expression in non-small-cell lung cancer. Oncotarget 8, 8738-8751 (2017).
54. 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).
55. Galluzzi, L, Buque, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunogenic cell death in cancer and infectious disease. Nat. Rev. Immunol. 17, 97-111 (2017).
56. 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).
57. Zhi, X. et al. RNA interference of ecto-5'-nucleotidase (CD73) inhibits human breast cancer cell growth and invasion. Clin. Exp. Metastasis 24, 439-448 (2007).
58. Turcotte, M. et al. CD73 is associated with poor prognosis in high-grade serous ovarian cancer. Cancer Res. 75, 4494-4503 (2015).
59. Sadej, R., Spychala, J. & Skladanowski, A. C. Expression of ecto-5'-nucleotidase (eN, CD73) in cell lines from various stages of human melanoma. Melanoma Res. 16, 213-222 (2006).
60. Terp, M. G. et al. 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, 4165-4173 (2013).
61. Wang, L. et al. Ecto-5'-nucleotidase promotes invasion, migration and adhesion of human breast cancer cells. J. Cancer Res. Clin. Oncol. 134, 365-372 (2008).
62. Merighi, S. et al. Adenosine receptors as mediators of both cell proliferation and cell death of cultured human melanoma cells. J. Invest. Dermatol. 119, 923-933 (2002).
63. Etique, N., Grillier-Vuissoz, I., Lecomte, J. & Flament, S. Crosstalk between adenosine receptor (A2A isoform) and ERα mediates ethanol action in MCF-7 breast cancer cells. Oncol. Rep. 21, 977-981 (2009).
64. Auchampach, J. A. Adenosine receptors and angiogenesis. Circ. Res. 101, 1075-1077 (2007).
65. Feng, L. et al. Vascular CD39/ENTPD1 directly promotes tumor cell growth by scavenging extracellular adenosine triphosphate. Neoplasia 13, 206-216 (2011).
66. Allard, B. et al. Anti-CD73 therapy impairs tumor angiogenesis. Int. J. Cancer. 134, 1466-1473 (2014).
67. 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).
68. Yang, Q., Du, J. & Zu, L. Overexpression of CD73 in prostate cancer is associated with lymph node metastasis. Pathol. Oncol. Res. 19, 811-814 (2013).
69. 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).
70. Srinivasan, S., Vannberg, F. O. & Dixon, J. B. Lymphatic transport of exosomes as a rapid route of information dissemination to the lymph node. Sci. Rep. 6, 24436 (2016).
71. Takedachi, M. et al. CD73-generated adenosine restricts lymphocyte migration into draining lymph nodes. J. Immunol. 180, 6288-6296 (2008).
72. Airas, L., Niemela, 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).
73. Speiser, D. E., Ho, P. C. & Verdeil, G. Regulatory circuits of T cell function in cancer. Nat. Rev. Immunol. 16, 599-611 (2016).
74. Guillerey, C., Huntington, N. D. & Smyth, M. J. Targeting natural killer cells in cancer immunotherapy. Nat. Immunol. 17, 1025-1036 (2016).
75. s protein-coupled adenosine receptor signaling and lytic function of activated NK cells. J. Immunol. 175, 4383-4391 (2005).
76. Ohta, A. et al. A2A adenosine receptor may allow expansion of T cells lacking effector functions in extracellular adenosine-rich microenvironments. J. Immunol. 183, 5487-5493 (2009).
77. +-infiltrating T cells contribute to adenosine-mediated T cell hyporesponsiveness. J. Immunol. 183, 6157-6166 (2009).
78. Ngiow, S. F. et al. Agonistic CD40 mAb-driven IL12 reverses resistance to anti-PD1 in a T-cell-rich tumor. Cancer Res. 76, 6266-6277 (2016).
79. + T cell anergy prevents autoimmunity and generates regulatory T cell precursors. Nat. Immunol. 17, 304-314 (2016).
80. Li, L. et al. Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury. J. Clin. Invest. 122, 3931-3942 (2012).
81. 2A-receptor-gene-deficient mice. Biochem. J. 354, 123-130 (2001).
82. Sevigny, C. P. et al. Activation of adenosine 2A receptors attenuates allograft rejection and alloantigen recognition. J. Immunol. 178, 4240-4249 (2007).
83. 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).
84. 2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 1 1 1, 251-259 (2008).
85. Sitkovsky, M. V., Kjaergaard, J., Lukashev, D. & Ohta, A. Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia. Clin. Cancer Res. 14, 5947-5952 (2008).
86. Montalbán 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).
87. de Lourdes Mora-Garcia, M. et al. Mesenchymal stromal cells derived from cervical cancer produce high amounts of adenosine to suppress cytotoxic T lymphocyte functions. J. Transl Med. 14, 302 (2016).
88. 2B receptor blockade slows growth of bladder and breast tumors. J. Immunol. 188, 198-205 (2012).
89. + regulatory T cells in cancers: a systematic review and meta-analysis. Sci. Rep. 5, 15179 (2015).
90. Choi, H. S. et al. The prognostic effects of tumor infiltrating regulatory T cells and myeloid derived suppressor cells assessed by multicolor flow cytometry in gastric cancer patients. Oncotarget 7, 7940-7951 (2016).
91. + regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway. Front. Immunol. 3, 190 (2012).
92. Zhang, B. et al. Circulating and tumor-infiltrating myeloid-derived suppressor cells in patients with colorectal carcinoma. PLoS ONE 8, e57114 (2013).
93. Novitskiy, S. V. et al. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 1 1 2, 1822-1831 (2008).
94. 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).
95. Ren, Z. H. et al. CD73 is associated with poor prognosis in HNSCC. Oncotarget 7, 61690-61702 (2016).
96. Kolachala, V. et al. TNF-α upregulates adenosine 2b (A2b) receptor expression and signaling in intestinal epithelial cells: a basis for A2bR overexpression in colitis. Cell. Mol. Life Sci. 62, 2647-2657 (2005).
97. Reinhardt, J. et al. MAPK signaling and inflammation link melanoma phenotype switching to induction of CD73 during immunotherapy. Cancer Res. 77, 4697-4709 (2017).
98. Hung, S. P., Yang, M. H., Tseng, K. F. & Lee, O. K. Hypoxia-induced secretion of TGF-β1 in mesenchymal stem cell promotes breast cancer cell progression. Cell Transplant. 22, 1869-1882 (2013).
99. Cortez, V. S. et al. Transforming growth factor-β signaling guides the differentiation of innate lymphoid cells in salivary glands. Immunity 44, 1127-1139 (2016).
100. Regateiro, F. S. et al. Generation of anti-inflammatory adenosine by leukocytes is regulated by TGF-β. Euro. J. Immunol. 41, 2955-2965 (2011).
101. Olivier, M., Hollstein, M. & Hainaut, P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb. Perspect. Biol. 2, a001008 (2010).
102. Wu, X. R. et al. High expression of CD73 as a poor prognostic biomarker in human colorectal cancer. J. Surg. Oncol. 106, 130-137 (2012).
103. Long, J. S. et al. Extracellular adenosine sensing-a metabolic cell death priming mechanism downstream of p53. Mol. Cell. 50, 394-406 (2013).
104. Emens, L. et al. CPI-444, an oral adenosine A2a receptor (A2aR) antagonist, demonstrates clinical activity in patients with advanced solid tumors [abstract]. Cancer Res. 77 (Suppl. 13), CT119 (2017).
105. Hay, C. M. et al. Targeting CD73 in the tumor microenvironment with MEDI9447. Oncoimmunology 5, e1208875 (2016).
106. + T cells and have profound effects in experimental tumor models [abstract]. Third CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference, 224 https://static1.squarespace.com/static/56dee71e555986fb3ae583e2/t/59ad08b1b8a 79b086c865d6c/1504512189107/CIMT- Abstracts-170904.pdf (2017).
107. 2A adenosine receptor bound to an antagonist. Science 322, 1211-1217 (2008).
108. Borodovsky, A. et al. Preclinical pharmacodynamics and antitumor activity of AZD4635, a novel adenosine 2A receptor inhibitor that reverses adenosine mediated T cell suppression [abstract]. Cancer Res. 77 (Suppl. 13), 5580 (2017).
109. Walters, M. J. et al. Characterization of the potent and selectiveA2aR antagonist AB928 for the treatment of cancer [abstract]. Cancer Res. 77 (Suppl. 13), 4572 (2017).
110. Fons, P. et al. Targeting the adenosine immunosuppressive pathway for cancer immunotherapy with small molecule agents [abstract]. Cancer Res. 77 (Suppl. 13), 3970 (2017).
111. Geoghegan, J. C. et al. Inhibition of CD73 AMP hydrolysis by a therapeutic antibody with a dual, non-competitive mechanism of action. mAbs 8, 454-467 (2016).
112. Piccione, E. C. et al. A novel CD73-blocking antibody reduces production of immunosuppressive adenosine and restores T cell function [abstract]. Cancer Res. 77 (Suppl. 13), 5577 (2017).
113. Gruenbacher, G. et al. Ecto-ATPase CD39 inactivates isoprenoid-derived Vγ9Vδ2 T cell phosphoantigens. Cell Rep. 16, 444-456 (2016).
114. Xu, S. et al. Synergy between the ectoenzymes CD39 and CD73 contributes to adenosinergic immunosuppression in human malignant gliomas. Neuro Oncol. 15, 1160-1172 (2013).
115. Serra, S. et al. CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death. Blood 118, 6141-6152 (2011).
116. Fernandez, P. et al. Extracellular generation of adenosine by the ectonucleotidases CD39 and CD73 promotes dermal fibrosis. Am. J. Pathol. 183, 1740-1746 (2013).
117. Di Virgilio, F. & Adinolfi, E. Extracellular purines, purinergic receptors and tumor growth. Oncogene 36, 293-303 (2017).
118. 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).
119. +-metabolizing ectoenzymes in remodeling tumor-host interactions: the human myeloma model. Cells 4, 520-537 (2015).
120. +-metabolizing ecto-enzymes shape tumor-host interactions: the chronic lymphocytic leukemia model. FEBS Lett. 585, 1514-1520 (2011).
121. Antonioli, L., Pacher, P., Vizi, E. S. & Hasko, G. CD39 and CD73 in immunity and inflammation. Trends Mol. Med. 19, 355-367 (2013).
122. + salvage pathway modulates cancer cell viability via p73. Cell Death Differ. 23, 669-680 (2016).
123. US National Library of Medicine. ClinicalTrial.gov https://clinicaltrials.gov/ct2/show/NCT02944565 (2017).
124. US National Library of Medicine. ClinicalTrial.gov https://clinicaltrials.gov/ct2/show/NCT01084252 (2017).
125. Zimmermann, H. Prostatic acid phosphatase, a neglected ectonucleotidase. Purinerg. Signal. 5, 273-275 (2009).
126. Yegutkin, G. G. et al. Consequences of the lack of CD73 and prostatic acid phosphatase in the lymphoid organs. Mediators Inflamm. 2014, 485743 (2014).
127. Kim, S. H. et al. Reassessment of alkaline phosphatase as serum tumor marker with high specificity in osteosarcoma. Cancer Med. 6, 1311-1322 (2017).
128. Rao, S. R. et al. Tumour-derived alkaline phosphatase regulates tumour growth, epithelial plasticity and disease-free survival in metastatic prostate cancer. Br. J. Cancer. 116, 227-236 (2017).
129. Pettengill, M. et al. Soluble ecto-5'-nucleotidase (5'-NT), alkaline phosphatase, and adenosine deaminase (ADA1) activities in neonatal blood favor elevated extracellular adenosine. J. Biol. Chem. 288, 27315-27326 (2013).
130. Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573-1577 (2011).
131. Iannone, R., Miele, L., Maiolino, P., Pinto, A. & Morello, S. Adenosine limits the therapeutic effectiveness of anti-CTLA4 mAb in a mouse melanoma model. Am. J. Cancer Res. 4, 172-181 (2014).
132. Gray, L. H., Conger, A. D., Ebert, M., Hornsey, S. & Scott, O. C. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br. J. Radiol. 26, 638-648 (1953).
133. Moeller, B. J., Cao, Y., Li, C. Y. & Dewhirst, M. W. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5, 429-441 (2004).
134. 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).
135. Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1-10 (2013).
136. Moriyama, K. & Sitkovsky, M. V. Adenosine A2A receptor is involved in cell surface expression of A2B receptor. J. Biol. Chem. 285, 39271-39288 (2010).
137. Stagg, J. et al. Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc. Natl Acad. Sci. USA 107, 1547-1552 (2010).
138. Tan, E. Y., Mujoomdar, M. & Blay, J. Adenosine down-regulates the surface expression of dipeptidyl peptidase IV on HT-29 human colorectal carcinoma cells: implications for cancer cell behavior. Am. J. Pathol. 165, 319-330 (2004).
139. 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).
140. Cai, X. Y. et al. Overexpression of CD39 in hepatocellular carcinoma is an independent indicator of poor outcome after radical resection. Medicine 95, e4989 (2016).
141. + ratio are associated with adverse prognosis in resectable gastric cancer. Int. J. Clin. Exp. Pathol. 8, 14757-14764 (2015).
142. Abousamra, N. K., Salah El-Din, M., Hamza Elzahaf, E. & Esmael, M. E. Ectonucleoside triphosphate diphosphohydrolase-1 (E-NTPDase1/CD39) as a new prognostic marker in chronic lymphocytic leukemia. Leuk. Lymphoma 56, 113-119 (2015).
143. Lu, X. X. et al. Expression and clinical significance of CD73 and hypoxia-inducible factor-1α in gastric carcinoma. World J. Gastroenterol. 19, 1912-1918 (2013).
144. Zhang, B. et al. The expression and clinical significance of CD73 molecule in human rectal adenocarcinoma. Tumour Biol. 36, 5459-5466 (2015).
145. Yu, Y. I. et al. Ecto-5'-nucleotidase expression is associated with the progression of renal cell carcinoma. Oncol. Lett. 9, 2485-2494 (2015).
146. Leclerc, B. G. et al. CD73 expression is an independent prognostic factor in prostate cancer. Clin. Cancer Res. 22, 158-166 (2016).
147. Wettstein, M. S. et al. CD73 predicts favorable prognosis in patients with nonmuscle-invasive urothelial bladder cancer. Dis. Markers 2015, 785461 (2015).
148. Bowser, J. L. et al. Loss of CD73-mediated actin polymerization promotes endometrial tumor progression. J. Clin. Invest. 126, 220-238 (2016).