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Adenosine Signaling in the Tumor Microenvironment

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Tumor Microenvironment

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1270))

Abstract

Adenosine, deriving from ATP released by dying cancer cells and then degradated in the tumor environment by CD39/CD73 enzyme axis, is linked to the generation of an immunosuppressed niche favoring the onset of neoplasia. Signals delivered by extracellular adenosine are detected and transduced by G-protein-coupled cell surface receptors, classified into four subtypes: A1, A2A, A2B, and A3. A critical role of this nucleoside is emerging in the modulation of several immune and nonimmune cells defining the tumor microenvironment, providing novel insights about the development of novel therapeutic strategies aimed at undermining the immune-privileged sites where cancer cells grow and proliferate.

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References

  1. Pitot HC (1993) The molecular biology of carcinogenesis. Cancer 72(3 Suppl):962–970

    Article  CAS  Google Scholar 

  2. Witz IP, Levy-Nissenbaum O (2006) The tumor microenvironment in the post-paget era. Cancer Lett 242(1):1–10

    Article  CAS  Google Scholar 

  3. Tuccitto A, Shahaj E, Vergani E, Ferro S, Huber V, Rodolfo M, Castelli C, Rivoltini L, Vallacchi V (2019) Immunosuppressive circuits in tumor microenvironment and their influence on cancer treatment efficacy. Virchows Arch Int J Pathol 474(4):407–420

    Article  CAS  Google Scholar 

  4. Blay J, White TD, Hoskin DW (1997) The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res 57(13):2602–2605

    CAS  Google Scholar 

  5. Hoskin DW, Butler JJ, Drapeau D, Haeryfar SM, Blay J (2002) Adenosine acts through an a3 receptor to prevent the induction of murine anti-cd3-activated killer t cells. Int J Cancer Journal international du cancer 99(3):386–395

    Article  CAS  Google Scholar 

  6. Hasko G, Linden J, Cronstein B, Pacher P (2008) Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov 7(9):759–770

    Article  CAS  Google Scholar 

  7. Antonioli L, Fornai M, Colucci R, Ghisu N, Tuccori M, Del Tacca M, Blandizzi C (2008) Regulation of enteric functions by adenosine: pathophysiological and pharmacological implications. Pharmacol Ther 120(3):233–253

    Article  CAS  Google Scholar 

  8. Longhi MS, Robson SC, Bernstein SH, Serra S, Deaglio S (2013) Biological functions of ecto-enzymes in regulating extracellular adenosine levels in neoplastic and inflammatory disease states. J Mol Med 91(2):165–172

    Article  CAS  Google Scholar 

  9. Hasko G, Cronstein BN (2004) Adenosine: an endogenous regulator of innate immunity. Trends Immunol 25(1):33–39

    Article  CAS  Google Scholar 

  10. Csoka B, Himer L, Selmeczy Z, Vizi ES, Pacher P, Ledent C, Deitch EA, Spolarics Z, Nemeth ZH, Hasko G (2008) Adenosine a2a receptor activation inhibits t helper 1 and t helper 2 cell development and effector function. FASEB J 22(10):3491–3499

    Article  CAS  Google Scholar 

  11. Himer L, Csoka B, Selmeczy Z, Koscso B, Pocza T, Pacher P, Nemeth ZH, Deitch EA, Vizi ES, Cronstein BN, Hasko G (2010) Adenosine a2a receptor activation protects cd4+ t lymphocytes against activation-induced cell death. FASEB J 24(8):2631–2640

    Article  CAS  Google Scholar 

  12. Sitkovsky MV, Kjaergaard J, Lukashev D, Ohta A (2008) Hypoxia-adenosinergic immunosuppression: tumor protection by t regulatory cells and cancerous tissue hypoxia. Clin Cancer Res 14(19):5947–5952

    Article  CAS  Google Scholar 

  13. Ohta A (2016) A metabolic immune checkpoint: Adenosine in tumor microenvironment. Front Immunol 7:109

    Article  CAS  Google Scholar 

  14. Sitkovsky MV, Hatfield S, Abbott R, Belikoff B, Lukashev D, Ohta A (2014) Hostile, hypoxia-a2-adenosinergic tumor biology as the next barrier to overcome for tumor immunologists. Cancer Immunol Res 2(7):598–605

    Article  CAS  Google Scholar 

  15. Linden J (2006) Adenosine metabolism and cancer. Focus on "adenosine downregulates dppiv on ht-29 colon cancer cells by stimulating protein tyrosine phosphatases and reducing erk1/2 activity via a novel pathway". Am J Physiol Cell Physiol 291(3):C405–C406

    Article  CAS  Google Scholar 

  16. Antonioli L, Novitskiy SV, Sachsenmeier KF, Fornai M, Blandizzi C, Hasko G (2017) Switching off cd73: a way to boost the activity of conventional and targeted antineoplastic therapies. Drug Discov Today 22:1686

    Article  CAS  Google Scholar 

  17. Antonioli L, Blandizzi C, Pacher P, Hasko G (2013) Immunity, inflammation and cancer: a leading role for adenosine. Nat Rev Cancer 13(12):842–857

    Article  CAS  Google Scholar 

  18. Allard B, Turcotte M, Spring K, Pommey S, Royal I, Stagg J (2014) Anti-cd73 therapy impairs tumor angiogenesis. Int J Cancer 134(6):1466–1473

    Article  CAS  Google Scholar 

  19. Hay CM, Sult E, Huang Q, Mulgrew K, Fuhrmann SR, McGlinchey KA, Hammond SA, Rothstein R, Rios-Doria J, Poon E, Holoweckyj N et al (2016) Targeting cd73 in the tumor microenvironment with medi9447. Onco Targets Ther 5(8):e1208875

    Google Scholar 

  20. Stagg J, Divisekera U, McLaughlin N, Sharkey J, Pommey S, Denoyer D, Dwyer KM, Smyth MJ (2010) Anti-cd73 antibody therapy inhibits breast tumor growth and metastasis. Proc Natl Acad Sci U S A 107(4):1547–1552

    Article  CAS  Google Scholar 

  21. Bavaresco L, Bernardi A, Braganhol E, Cappellari AR, Rockenbach L, Farias PF, Wink MR, Delgado-Canedo A, Battastini AM (2008) The role of ecto-5′-nucleotidase/cd73 in glioma cell line proliferation. Mol Cell Biochem 319(1–2):61–68

    Article  CAS  Google Scholar 

  22. Tan EY, Richard CL, Zhang H, Hoskin DW, Blay J (2006) Adenosine downregulates dppiv on ht-29 colon cancer cells by stimulating protein tyrosine phosphatase(s) and reducing erk1/2 activity via a novel pathway. Am J Physiol Cell Physiol 291(3):C433–C444

    Article  CAS  Google Scholar 

  23. Pennycooke M, Chaudary N, Shuralyova I, Zhang Y, Coe IR (2001) Differential expression of human nucleoside transporters in normal and tumor tissue. Biochem Biophys Res Commun 280(3):951–959

    Article  CAS  Google Scholar 

  24. Damaraju VL, Damaraju S, Young JD, Baldwin SA, Mackey J, Sawyer MB, Cass CE (2003) Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy. Oncogene 22(47):7524–7536

    Article  CAS  Google Scholar 

  25. Antonioli L, Colucci R, La Motta C, Tuccori M, Awwad O, Da Settimo F, Blandizzi C, Fornai M (2012) Adenosine deaminase in the modulation of immune system and its potential as a novel target for treatment of inflammatory disorders. Curr Drug Targets 13(6):842–862

    Article  CAS  Google Scholar 

  26. Antonioli L, Fornai M, Colucci R, Ghisu N, Blandizzi C, Del Tacca M (2006) A2a receptors mediate inhibitory effects of adenosine on colonic motility in the presence of experimental colitis. Inflamm Bowel Dis 12(2):117–122

    Article  Google Scholar 

  27. Antonioli L, Fornai M, Colucci R, Awwad O, Ghisu N, Tuccori M, Del Tacca M, Blandizzi C (2011) Differential recruitment of high affinity a1 and a2a adenosine receptors in the control of colonic neuromuscular function in experimental colitis. Eur J Pharmacol 650(2–3):639–649

    Article  CAS  Google Scholar 

  28. Long JS, Crighton D, O’Prey J, Mackay G, Zheng L, Palmer TM, Gottlieb E, Ryan KM (2013) Extracellular adenosine sensing-a metabolic cell death priming mechanism downstream of p53. Mol Cell 50(3):394–406

    Article  CAS  Google Scholar 

  29. Baldwin SA, Beal PR, Yao SY, King AE, Cass CE, Young JD (2004) The equilibrative nucleoside transporter family, slc29. Pflugers Arch Eur J Physiol 447(5):735–743

    Article  CAS  Google Scholar 

  30. Aghaei M, Karami-Tehrani F, Panjehpour M, Salami S, Fallahian F (2012) Adenosine induces cell-cycle arrest and apoptosis in androgen-dependent and -independent prostate cancer cell lines, lncap-fgc-10, du-145, and pc3. Prostate 72(4):361–375

    Article  CAS  Google Scholar 

  31. Yang D, Yaguchi T, Yamamoto H, Nishizaki T (2007) Intracellularly transported adenosine induces apoptosis in huh-7 human hepatoma cells by downregulating c-flip expression causing caspase-3/−8 activation. Biochem Pharmacol 73(10):1665–1675

    Article  CAS  Google Scholar 

  32. Tamura K, Kanno T, Fujita Y, Gotoh A, Nakano T, Nishizaki T (2012) A(2a) adenosine receptor mediates hepg2 cell apoptosis by downregulating bcl-x(l) expression and upregulating bid expression. J Cell Biochem 113(5):1766–1775

    CAS  Google Scholar 

  33. Yang D, Yaguchi T, Lim CR, Ishizawa Y, Nakano T, Nishizaki T (2010) Tuning of apoptosis-mediator gene transcription in hepg2 human hepatoma cells through an adenosine signal. Cancer Lett 291(2):225–229

    Article  CAS  Google Scholar 

  34. Morello S, Sorrentino R, Porta A, Forte G, Popolo A, Petrella A, Pinto A (2009) Cl-ib-meca enhances trail-induced apoptosis via the modulation of nf-kappab signalling pathway in thyroid cancer cells. J Cell Physiol 221(2):378–386

    Article  CAS  Google Scholar 

  35. Nogi Y, Kanno T, Nakano T, Fujita Y, Tabata C, Fukuoka K, Gotoh A, Nishizaki T (2012) Amp converted from intracellularly transported adenosine upregulates p53 expression to induce malignant pleural mesothelioma cell apoptosis. Cell Physiol Biochem 30(1):61–74

    Article  CAS  Google Scholar 

  36. Yang D, Yaguchi T, Nagata T, Gotoh A, Dovat S, Song C, Nishizaki T (2011) Amid mediates adenosine-induced caspase-independent huh-7 cell apoptosis. Cell Physiol Biochem 27(1):37–44

    Article  CAS  Google Scholar 

  37. Antonioli L, Colucci R, Pellegrini C, Giustarini G, Tuccori M, Blandizzi C, Fornai M (2013) The role of purinergic pathways in the pathophysiology of gut diseases: pharmacological modulation and potential therapeutic applications. Pharmacol Ther 139(2):157–188

    Article  CAS  Google Scholar 

  38. Hoskin DW, Mader JS, Furlong SJ, Conrad DM, Blay J (2008) Inhibition of t cell and natural killer cell function by adenosine and its contribution to immune evasion by tumor cells (review). Int J Oncol 32(3):527–535

    CAS  Google Scholar 

  39. Mato JM, Martinez-Chantar ML, Lu SC (2008) Methionine metabolism and liver disease. Annu Rev Nutr 28:273–293

    Article  CAS  Google Scholar 

  40. da Silva CG, Jarzyna R, Specht A, Kaczmarek E (2006) Extracellular nucleotides and adenosine independently activate amp-activated protein kinase in endothelial cells: involvement of p2 receptors and adenosine transporters. Circ Res 98(5):e39–e47

    Article  CAS  Google Scholar 

  41. Boison D (2013) Adenosine kinase: exploitation for therapeutic gain. Pharmacol Rev 65(3):906–943

    Article  CAS  Google Scholar 

  42. Félétou M (2011) The endothelium: part 1: multiple functions of the endothelial cells—focus on endothelium-derived vasoactive mediators. Morgan & Claypool Life Sciences, San Rafael

    Book  Google Scholar 

  43. Hida K, Maishi N, Annan DA, Hida Y (2018) Contribution of tumor endothelial cells in cancer progression. Int J Mol Sci 19(5):1272

    Article  CAS  Google Scholar 

  44. Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473(7347):298–307

    Article  CAS  Google Scholar 

  45. Narravula S, Lennon PF, Mueller BU, Colgan SP (2000) Regulation of endothelial cd73 by adenosine: paracrine pathway for enhanced endothelial barrier function. J Immunol 165(9):5262–5268

    Article  CAS  Google Scholar 

  46. Acurio J, Herlitz K, Troncoso F, Aguayo C, Bertoglia P, Escudero CJPS (2017) Adenosine a2a receptor regulates expression of vascular endothelial growth factor in feto-placental endothelium from normal and late-onset pre-eclamptic pregnancies. Purinergic Signal 13(1):51–60

    Article  CAS  Google Scholar 

  47. Khoa ND, Montesinos MC, Williams AJ, Kelly M, Cronstein BN (2003) Th1 cytokines regulate adenosine receptors and their downstream signaling elements in human microvascular endothelial cells. J Immunol 171(8):3991–3998

    Article  CAS  Google Scholar 

  48. Feoktistov I, Goldstein AE, Ryzhov S, Zeng D, Belardinelli L, Voyno-Yasenetskaya T, Biaggioni I (2002) Differential expression of adenosine receptors in human endothelial cells. Circ Res 90(5):531–538

    Article  CAS  Google Scholar 

  49. Grant MB, Tarnuzzer RW, Caballero S, Ozeck MJ, Davis MI, Spoerri PE, Feoktistov I, Biaggioni I, Shryock JC, Belardinelli L (1999) Adenosine receptor activation induces vascular endothelial growth factor in human retinal endothelial cells. Circ Res 85(8):699–706

    Article  CAS  Google Scholar 

  50. Canale FP, Ramello MC, Núñez N, Furlan CLA, Bossio SN, Serrán MG, Boari JT, del Castillo A, Ledesma M, Sedlik C, Piaggio E et al (2018) Cd39 expression defines cell exhaustion in tumor-infiltrating cd8<sup>+</sup> t cells. Cancer Res 78(1):115–128

    Article  CAS  Google Scholar 

  51. Katamura K, Shintaku N, Yamauchi Y, Fukui T, Ohshima Y, Mayumi M, Furusho K (1995) Prostaglandin e2 at priming of naive cd4+ t cells inhibits acquisition of ability to produce ifn-gamma and il-2, but not il-4 and il-5. J Immunol 155(10):4604–4612

    Article  CAS  Google Scholar 

  52. Henttinen T, Jalkanen S, Yegutkin GG (2003) Adherent leukocytes prevent adenosine formation and impair endothelial barrier function by ecto-5′-nucleotidase/cd73-dependent mechanism. J Biol Chem 278(27):24888–24895

    Article  CAS  Google Scholar 

  53. Bouma MG, Wildenberg FAvd, Buurman WA (1996) Adenosine inhibits cytokine release and expression of adhesion molecules by activated human endothelial cells. Am J Physio 270(2):C522–C529

    Article  CAS  Google Scholar 

  54. Grünewald JKG, Ridley AJ (2010) Cd73 represses pro-inflammatory responses in human endothelial cells. J Inflamm 7(1):10

    Article  CAS  Google Scholar 

  55. Walker G, Langheinrich AC, Dennhauser E, Bohle RM, Dreyer T, Kreuzer J, Tillmanns H, Braun-Dullaeus RC, Haberbosch W (1999) 3-deazaadenosine prevents adhesion molecule expression and atherosclerotic lesion formation in the aortas of c57bl/6j mice. Arterioscler Thromb Vasc Biol 19(11):2673–2679

    Article  CAS  Google Scholar 

  56. Jackson SW, Hoshi T, Wu Y, Sun X, Enjyoji K, Cszimadia E, Sundberg C, Robson SC (2007) Disordered purinergic signaling inhibits pathological angiogenesis in cd39/entpd1-null mice. Am J Pathol 171(4):1395–1404

    Article  CAS  Google Scholar 

  57. Sun X, Wu Y, Gao W, Enjyoji K, Csizmadia E, Muller CE, Murakami T, Robson SC (2010) Cd39/entpd1 expression by cd4+foxp3+ regulatory t cells promotes hepatic metastatic tumor growth in mice. Gastroenterology 139(3):1030–1040

    Article  CAS  Google Scholar 

  58. Feng L, Sun X, Csizmadia E, Han L, Bian S, Murakami T, Wang X, Robson SC, Wu Y (2011) Vascular cd39/entpd1 directly promotes tumor cell growth by scavenging extracellular adenosine triphosphate. Neoplasia (New York, NY) 13(3):206–216

    Article  CAS  Google Scholar 

  59. Wang L, Tang S, Wang Y, Xu S, Yu J, Zhi X, Ou Z, Yang J, Zhou P, Shao Z (2013) Ecto-5′-nucleotidase (cd73) promotes tumor angiogenesis. Clin Exp Metastasis 30(5):671–680

    Article  CAS  Google Scholar 

  60. Wang L, Fan J, Thompson LF, Zhang Y, Shin T, Curiel TJ, Zhang B (2011) Cd73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. J Clin Invest 121(6):2371–2382

    Article  CAS  Google Scholar 

  61. Ohta A, Gorelik E, Prasad SJ, Ronchese F, Lukashev D, Wong MK, Huang X, Caldwell S, Liu K, Smith P, Chen JF et al (2006) A2a adenosine receptor protects tumors from antitumor t cells. Proc Natl Acad Sci U S A 103(35):13132–13137

    Article  CAS  Google Scholar 

  62. Ryzhov S, Novitskiy SV, Zaynagetdinov R, Goldstein AE, Carbone DP, Biaggioni I, Dikov MM, Feoktistov I (2008) Host a(2b) adenosine receptors promote carcinoma growth. Neoplasia (New York, NY) 10(9):987–995

    Article  CAS  Google Scholar 

  63. Sorrentino C, Miele L, Porta A, Pinto A, Morello S (2015) Myeloid-derived suppressor cells contribute to a2b adenosine receptor-induced vegf production and angiogenesis in a mouse melanoma model. Oncotarget 6(29):27478–27489

    Article  Google Scholar 

  64. Wilkat M, Bast H, Drees R, Dünser J, Mahr A, Azoitei N, Marienfeld R, Frank F, Brhel M, Ushmorov A, Greve J et al Adenosine receptor 2b activity promotes autonomous growth, migration as well as vascularization of head and neck squamous cell carcinoma cells. n/a(n/a)

    Google Scholar 

  65. Hatfield SM, Kjaergaard J, Lukashev D, Belikoff B, Schreiber TH, Sethumadhavan S, Abbott R, Philbrook P, Thayer M, Shujia D, Rodig S et al (2014) Systemic oxygenation weakens the hypoxia and hypoxia inducible factor 1alpha-dependent and extracellular adenosine-mediated tumor protection. J Mol Med 92(12):1283–1292

    Article  CAS  Google Scholar 

  66. Yamazaki T, Mukouyama YS (2018) Tissue specific origin, development, and pathological perspectives of pericytes. Front Cardiovasc Med 5:78

    Article  CAS  Google Scholar 

  67. Dias Moura Prazeres PH, Sena IFG, Borges IDT, de Azevedo PO, Andreotti JP, de Paiva AE, de Almeida VM, de Paula Guerra DA, Pinheiro Dos Santos GS, Mintz A, Delbono O et al (2017) Pericytes are heterogeneous in their origin within the same tissue. Dev Biol 427(1):6–11

    Article  CAS  Google Scholar 

  68. Bergers G, Song S (2005) The role of pericytes in blood-vessel formation and maintenance. Neuro-Oncology 7(4):452–464

    Article  CAS  Google Scholar 

  69. Ribatti D, Nico B, Crivellato E (2011) The role of pericytes in angiogenesis. Int J Dev Biol 55(3):261–268

    Article  CAS  Google Scholar 

  70. Gerhardt H, Betsholtz C (2003) Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res 314(1):15–23

    Article  Google Scholar 

  71. Balabanov R, Washington R, Wagnerova J, Dore-Duffy P (1996) Cns microvascular pericytes express macrophage-like function, cell surface integrin alpha m, and macrophage marker ed-2. Microvasc Res 52(2):127–142

    Article  CAS  Google Scholar 

  72. Pieper C, Marek JJ, Unterberg M, Schwerdtle T, Galla HJ (2014) Brain capillary pericytes contribute to the immune defense in response to cytokines or lps in vitro. Brain Res 1550:1–8

    Article  CAS  Google Scholar 

  73. Pieper C, Pieloch P, Galla HJ (2013) Pericytes support neutrophil transmigration via interleukin-8 across a porcine co-culture model of the blood-brain barrier. Brain Res 1524:1–11

    Article  CAS  Google Scholar 

  74. Lindblom P, Gerhardt H, Liebner S, Abramsson A, Enge M, Hellstrom M, Backstrom G, Fredriksson S, Landegren U, Nystrom HC, Bergstrom G et al (2003) Endothelial pdgf-b retention is required for proper investment of pericytes in the microvessel wall. Genes Dev 17(15):1835–1840

    Article  CAS  Google Scholar 

  75. Huang FJ, You WK, Bonaldo P, Seyfried TN, Pasquale EB, Stallcup WB (2010) Pericyte deficiencies lead to aberrant tumor vascularizaton in the brain of the ng2 null mouse. Dev Biol 344(2):1035–1046

    Article  CAS  Google Scholar 

  76. Raza A, Franklin MJ, Dudek AZ (2010) Pericytes and vessel maturation during tumor angiogenesis and metastasis. Am J Hematol 85(8):593–598

    Article  CAS  Google Scholar 

  77. Sun H, Guo D, Su Y, Yu D, Wang Q, Wang T, Zhou Q, Ran X, Zou Z (2014) Hyperplasia of pericytes is one of the main characteristics of microvascular architecture in malignant glioma. PLoS One 9(12):e114246

    Article  CAS  Google Scholar 

  78. Ribeiro AL, Okamoto OK (2015) Combined effects of pericytes in the tumor microenvironment. Stem Cells Int 2015:868475

    Article  Google Scholar 

  79. Cao Y, Zhang ZL, Zhou M, Elson P, Rini B, Aydin H, Feenstra K, Tan MH, Berghuis B, Tabbey R, Resau JH et al (2013) Pericyte coverage of differentiated vessels inside tumor vasculature is an independent unfavorable prognostic factor for patients with clear cell renal cell carcinoma. Cancer 119(2):313–324

    Article  CAS  Google Scholar 

  80. Zhang L, Nishihara H, Kano MR (2012) Pericyte-coverage of human tumor vasculature and nanoparticle permeability. Biol Pharm Bull 35(5):761–766

    Article  CAS  Google Scholar 

  81. Cooke VG, LeBleu VS, Keskin D, Khan Z, O’Connell JT, Teng Y, Duncan MB, Xie L, Maeda G, Vong S, Sugimoto H et al (2012) Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell 21(1):66–81

    Article  CAS  Google Scholar 

  82. Hellstrom M, Gerhardt H, Kalen M, Li X, Eriksson U, Wolburg H, Betsholtz C (2001) Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 153(3):543–553

    Article  CAS  Google Scholar 

  83. Lindahl P, Johansson BR, Leveen P, Betsholtz C (1997) Pericyte loss and microaneurysm formation in pdgf-b-deficient mice. Science 277(5323):242–245

    Article  CAS  Google Scholar 

  84. Birbrair A, Zhang T, Wang ZM, Messi ML, Olson JD, Mintz A, Delbono O (2014) Type-2 pericytes participate in normal and tumoral angiogenesis. Am J Physiol Cell Physiol 307(1):C25–C38

    Article  CAS  Google Scholar 

  85. Sweeney MD, Ayyadurai S, Zlokovic BV (2016) Pericytes of the neurovascular unit: key functions and signaling pathways. Nat Neurosci 19(6):771–783

    Article  CAS  Google Scholar 

  86. Li Q, Puro DG (2001) Adenosine activates atp-sensitive k(+) currents in pericytes of rat retinal microvessels: role of a1 and a2a receptors. Brain Res 907(1–2):93–99

    Article  CAS  Google Scholar 

  87. Sugiyama T, Kawamura H, Yamanishi S, Kobayashi M, Katsumura K, Puro DG (2005) Regulation of p2x7-induced pore formation and cell death in pericyte-containing retinal microvessels. Am J Physiol Cell Physiol 288(3):C568–C576

    Article  CAS  Google Scholar 

  88. Kawamura H, Sugiyama T, Wu DM, Kobayashi M, Yamanishi S, Katsumura K, Puro DG (2003) Atp: a vasoactive signal in the pericyte-containing microvasculature of the rat retina. J Physiol 551(Pt 3):787–799

    Article  CAS  Google Scholar 

  89. Ceruti S, Colombo L, Magni G, Vigano F, Boccazzi M, Deli MA, Sperlagh B, Abbracchio MP, Kittel A (2011) Oxygen-glucose deprivation increases the enzymatic activity and the microvesicle-mediated release of ectonucleotidases in the cells composing the blood-brain barrier. Neurochem Int 59(2):259–271

    Article  CAS  Google Scholar 

  90. Zhu C, Chrifi I, Mustafa D, van der Weiden M, Leenen PJM, Duncker DJ, Kros JM, Cheng C (2017) Cecr1-mediated cross talk between macrophages and vascular mural cells promotes neovascularization in malignant glioma. Oncogene 36(38):5356–5368

    Article  CAS  Google Scholar 

  91. Zhu C, Mustafa DAM, Krebber MM, Chrifi I, Leenen PJM, Duncker DJ, Dekker L, Luider TM, Kros JM, Cheng C (2018) Comparative proteomic analysis of cat eye syndrome critical region protein 1- function in tumor-associated macrophages and immune response regulation of glial tumors. Oncotarget 9(71):33500–33514

    Article  Google Scholar 

  92. Umemura N, Saio M, Suwa T, Kitoh Y, Bai J, Nonaka K, Ouyang GF, Okada M, Balazs M, Adany R, Shibata T et al (2008) Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear m1- and m2-type characteristics. J Leukoc Biol 83(5):1136–1144

    Article  CAS  Google Scholar 

  93. Xuan W, Qu Q, Zheng B, Xiong S, Fan GH (2015) The chemotaxis of m1 and m2 macrophages is regulated by different chemokines. J Leukoc Biol 97(1):61–69

    Article  CAS  Google Scholar 

  94. Linde N, Lederle W, Depner S, van Rooijen N, Gutschalk CM, Mueller MM (2012) Vascular endothelial growth factor-induced skin carcinogenesis depends on recruitment and alternative activation of macrophages. J Pathol 227(1):17–28

    Article  CAS  Google Scholar 

  95. Sidibe A, Ropraz P, Jemelin S, Emre Y, Poittevin M, Pocard M, Bradfield PF, Imhof BA (2018) Angiogenic factor-driven inflammation promotes extravasation of human proangiogenic monocytes to tumours. Nat Commun 9(1):355

    Article  CAS  Google Scholar 

  96. Hughes R, Qian BZ, Rowan C, Muthana M, Keklikoglou I, Olson OC, Tazzyman S, Danson S, Addison C, Clemons M, Gonzalez-Angulo AM et al (2015) Perivascular m2 macrophages stimulate tumor relapse after chemotherapy. Cancer Res 75(17):3479–3491

    Article  CAS  Google Scholar 

  97. Chanmee T, Ontong P, Konno K, Itano N (2014) Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel) 6(3):1670–1690

    Article  CAS  Google Scholar 

  98. Ojalvo LS, Whittaker CA, Condeelis JS, Pollard JW (2010) Gene expression analysis of macrophages that facilitate tumor invasion supports a role for wnt-signaling in mediating their activity in primary mammary tumors. J Immunol 184(2):702–712

    Article  CAS  Google Scholar 

  99. Sica A, Schioppa T, Mantovani A, Allavena P (2006) Tumour-associated macrophages are a distinct m2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer (Oxford, England : 1990) 42(6):717–727

    Article  CAS  Google Scholar 

  100. Haskó G, Pacher P (2012) Regulation of macrophage function by adenosine. Arterioscler Thromb Vasc Biol 32(4):865–869

    Article  CAS  Google Scholar 

  101. Csoka B, Selmeczy Z, Koscso B, Nemeth ZH, Pacher P, Murray PJ, Kepka-Lenhart D, Morris SM Jr, Gause WC, Leibovich SJ, Hasko G (2012) Adenosine promotes alternative macrophage activation via a2a and a2b receptors. FASEB J 26(1):376–386

    Article  CAS  Google Scholar 

  102. Haskó G, Kuhel DG, Chen J-F, Schwarzschild MA, Deitch EA, Mabley JG, Marton A, Szabó C (2000) Adenosine inhibits il-12 and tnf-α production via adenosine a2a receptor-dependent and independent mechanisms. FASEB J 14(13):2065–2074

    Article  Google Scholar 

  103. Costales MG, Alam MS, Cavanaugh C, Williams KM (2018) Extracellular adenosine produced by ecto-5′-nucleotidase (cd73) regulates macrophage pro-inflammatory responses, nitric oxide production, and favors salmonella persistence. Nitric Oxide 72:7–15

    Article  CAS  Google Scholar 

  104. Si QS, Nakamura Y, Kataoka K (1997) Adenosine inhibits superoxide production in rat peritoneal macrophages via elevation of camp level. Immunopharmacology 36(1):1–7

    Article  CAS  Google Scholar 

  105. Ramanathan M, Pinhal-Enfield G, Hao I, Leibovich SJ (2007) Synergistic up-regulation of vascular endothelial growth factor (vegf) expression in macrophages by adenosine a2a receptor agonists and endotoxin involves transcriptional regulation via the hypoxia response element in the vegf promoter. Mol Biol Cell 18(1):14–23

    Article  CAS  Google Scholar 

  106. Yegutkin GG, Marttila-Ichihara F, Karikoski M, Niemela J, Laurila JP, Elima K, Jalkanen S, Salmi M (2011) Altered purinergic signaling in cd73-deficient mice inhibits tumor progression. Eur J Immunol 41(5):1231–1241

    Article  CAS  Google Scholar 

  107. Cekic C, Day Y-J, Sag D, Linden J (2014) Myeloid expression of adenosine a<sub>2a</sub> receptor suppresses t and nk cell responses in the solid tumor microenvironment. Cancer Res 74(24):7250–7259

    Article  CAS  Google Scholar 

  108. Montalban Del Barrio I, Penski C, Schlahsa L, Stein RG, Diessner J, Wockel A, Dietl J, Lutz MB, Mittelbronn M, Wischhusen J, Hausler SFM (2016) 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

    Article  Google Scholar 

  109. Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392(6673):245–252

    Article  CAS  Google Scholar 

  110. Tran Janco JM, Lamichhane P, Karyampudi L, Knutson KL (2015) Tumor-infiltrating dendritic cells in cancer pathogenesis. J Immunol 194(7):2985–2991

    Article  CAS  Google Scholar 

  111. Dickenson JM, Reeder S, Rees B, Alexander S, Kendall D (2003) Functional expression of adenosine a2a and a3 receptors in the mouse dendritic cell line xs-106. Eur J Pharmacol 474(1):43–51

    Article  CAS  Google Scholar 

  112. Challier J, Bruniquel D, Sewell AK, Laugel B (2013) Adenosine and camp signalling skew human dendritic cell differentiation towards a tolerogenic phenotype with defective cd8(+) t-cell priming capacity. Immunology 138(4):402–410

    Article  CAS  Google Scholar 

  113. Novitskiy SV, Ryzhov S, Zaynagetdinov R, Goldstein AE, Huang Y, Tikhomirov OY, Blackburn MR, Biaggioni I, Carbone DP, Feoktistov I, Dikov MM (2008) Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 112(5):1822–1831

    Article  CAS  Google Scholar 

  114. Addi AB, Lefort A, Hua X, Libert F, Communi D, Ledent C, Macours P, Tilley SL, Boeynaems J-M, Robaye B (2008) Modulation of murine dendritic cell function by adenine nucleotides and adenosine: involvement of the a2b receptor. Eur J Immunol 38(6):1610–1620

    Article  CAS  Google Scholar 

  115. Panther E, Idzko M, Herouy Y, Rheinen H, Gebicke-Haerter PJ, Mrowietz U, Dichmann S, Norgauer J (2001) Expression and function of adenosine receptors in human dendritic cells. FASEB J 15(11):1963–1970

    Article  CAS  Google Scholar 

  116. Panther E, Corinti S, Idzko M, Herouy Y, Napp M, la Sala A, Girolomoni G, Norgauer J (2003) Adenosine affects expression of membrane molecules, cytokine and chemokine release, and the t-cell stimulatory capacity of human dendritic cells. Blood 101(10):3985–3990

    Article  CAS  Google Scholar 

  117. Naval-Macabuhay I, Casanova V, Navarro G, Garcia F, Leon A, Miralles L, Rovira C, Martinez-Navio JM, Gallart T, Mallol J, Gatell JM et al (2016) Adenosine deaminase regulates treg expression in autologous t cell-dendritic cell cocultures from patients infected with hiv-1. J Leukoc Biol 99(2):349–359

    Article  CAS  Google Scholar 

  118. Wilson JM, Ross WG, Agbai ON, Frazier R, Figler RA, Rieger J, Linden J, Ernst PB (2009) The a2b adenosine receptor impairs the maturation and immunogenicity of dendritic cells. J Immunol 182(8):4616–4623

    Article  CAS  Google Scholar 

  119. Cekic C, Sag D, Li Y, Theodorescu D, Strieter RM, Linden J (2012) Adenosine a2b receptor blockade slows growth of bladder and breast tumors. J Immunol 188(1):198–205

    Article  CAS  Google Scholar 

  120. Ryzhov SV, Pickup MW, Chytil A, Gorska AE, Zhang Q, Owens P, Feoktistov I, Moses HL, Novitskiy SV (2014) Role of tgf-beta signaling in generation of cd39+cd73+ myeloid cells in tumors. J Immunol 193(6):3155–3164

    Article  CAS  Google Scholar 

  121. Michaud M, Martins I, Sukkurwala AQ, Adjemian S, Ma Y, Pellegatti P, Shen S, Kepp O, Scoazec M, Mignot G, Rello-Varona S et al (2011) Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334(6062):1573–1577

    Article  CAS  Google Scholar 

  122. Wennerberg E, Kawashima N, Demaria SJJfIoC (2015) Adenosine regulates radiation therapy-induced anti-tumor immunity. J Immunother Cancer 3(2):P378

    Article  Google Scholar 

  123. Wennerberg E, Cronstein B, Formenti SC, Demaria S (2017) Adenosine generation limits radiation-induced tumor immunogenicity by abrogating recruitment and activation of cd103<sup>+</sup> dcs. J Immunol 198(1 Supplement):154.156–154.156

    Google Scholar 

  124. Jordan KR, Kapoor P, Spongberg E, Tobin RP, Gao D, Borges VF, McCarter MD (2017) Immunosuppressive myeloid-derived suppressor cells are increased in splenocytes from cancer patients. Cancer Immunol Immunother CII 66(4):503–513

    Article  CAS  Google Scholar 

  125. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12(4):253–268

    Article  CAS  Google Scholar 

  126. Bronte V, Chappell DB, Apolloni E, Cabrelle A, Wang M, Hwu P, Restifo NP (1999) Unopposed production of granulocyte-macrophage colony-stimulating factor by tumors inhibits cd8+ t cell responses by dysregulating antigen-presenting cell maturation. J Immunol 162(10):5728–5737

    Article  CAS  Google Scholar 

  127. Morales JK, Kmieciak M, Knutson KL, Bear HD, Manjili MH (2010) Gm-csf is one of the main breast tumor-derived soluble factors involved in the differentiation of cd11b-gr1- bone marrow progenitor cells into myeloid-derived suppressor cells. Breast Cancer Res Treat 123(1):39–49

    Article  CAS  Google Scholar 

  128. Kusmartsev S, Gabrilovich DI (2003) Inhibition of myeloid cell differentiation in cancer: the role of reactive oxygen species. J Leukoc Biol 74(2):186–196

    Article  CAS  Google Scholar 

  129. Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng P, Cho HI, Celis E, Quiceno DG, Padhya T, McCaffrey TV et al (2010) Hif-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med 207(11):2439–2453

    Article  CAS  Google Scholar 

  130. Ryzhov S, Novitskiy SV, Goldstein AE, Biktasova A, Blackburn MR, Biaggioni I, Dikov MM, Feoktistov I (2011) Adenosinergic regulation of the expansion and immunosuppressive activity of cd11b+gr1+ cells. J Immunol 187(11):6120–6129

    Article  CAS  Google Scholar 

  131. Iannone R, Miele L, Maiolino P, Pinto A, Morello S (2013) 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

    Article  CAS  Google Scholar 

  132. Morello S, Miele L (2014) Targeting the adenosine a2b receptor in the tumor microenvironment overcomes local immunosuppression by myeloid-derived suppressor cells. Oncoimmunology. 2014 Feb 14;3:e27989. https://doi.org/10.4161/onci.27989. eCollection 2014.

  133. Li J, Wang L, Chen X, Li L, Li Y, Ping Y, Huang L, Yue D, Zhang Z, Wang F, Li F et al (2017) Cd39/cd73 upregulation on myeloid-derived suppressor cells via tgf-beta-mtor-hif-1 signaling in patients with non-small cell lung cancer. Onco Targets Ther 6(6):e1320011

    Google Scholar 

  134. Li L, Wang L, Li J, Fan Z, Yang L, Zhang Z, Zhang C, Yue D, Qin G, Zhang T, Li F et al (2018) Metformin-induced reduction of cd39 and cd73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer. Cancer Res 78(7):1779–1791

    Article  CAS  Google Scholar 

  135. Limagne E, Euvrard R, Thibaudin M, Rébé C, Derangère V, Chevriaux A, Boidot R, Végran F, Bonnefoy N, Vincent J, Bengrine-Lefevre L et al (2016) 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(18):5241–5252

    Article  CAS  Google Scholar 

  136. Turcotte M, Allard D, Mittal D, Bareche Y, Buisseret L, Jose V, Pommey S, Delisle V, Loi S, Joensuu H, Kellokumpu-Lehtinen PL et al (2017) Cd73 promotes resistance to her2/erbb2 antibody therapy. Cancer Res 77(20):5652–5663

    Article  CAS  Google Scholar 

  137. Oelkrug C, Ramage JM (2014) Enhancement of t cell recruitment and infiltration into tumours. Clin Exp Immunol 178(1):1–8

    Article  CAS  Google Scholar 

  138. Gajewski TF, Schreiber H, Fu Y-X (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14(10):1014–1022

    Article  CAS  Google Scholar 

  139. Mlecnik B, Tosolini M, Kirilovsky A, Berger A, Bindea G, Meatchi T, Bruneval P, Trajanoski Z, Fridman WH, Pages F, Galon J (2011) Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol 29(6):610–618

    Article  Google Scholar 

  140. Crimeen-Irwin B, Scalzo K, Gloster S, Mottram PL, Plebanski M (2005) Failure of immune homeostasis -- the consequences of under and over reactivity. Curr Drug Targets Immune Endocr Metabol Disord 5(4):413–422

    Article  CAS  Google Scholar 

  141. Allard B, Longhi MS, Robson SC, Stagg J (2017) The ectonucleotidases cd39 and cd73: novel checkpoint inhibitor targets. Immunol Rev 276(1):121–144

    Article  CAS  Google Scholar 

  142. Antonioli L, Pacher P, Vizi ES, Hasko G (2013) Cd39 and cd73 in immunity and inflammation. Trends Mol Med 19(6):355–367

    Article  CAS  Google Scholar 

  143. Zarek PE, Huang CT, Lutz ER, Kowalski J, Horton MR, Linden J, Drake CG, Powell JD (2008) A2a receptor signaling promotes peripheral tolerance by inducing t-cell anergy and the generation of adaptive regulatory t cells. Blood 111(1):251–259

    Article  CAS  Google Scholar 

  144. Mirabet M, Herrera C, Cordero OJ, Mallol J, Lluis C, Franco R (1999) Expression of a2b adenosine receptors in human lymphocytes: their role in t cell activation. J Cell Sci 112(Pt 4):491–502

    Article  CAS  Google Scholar 

  145. Erdmann AA, Gao ZG, Jung U, Foley J, Borenstein T, Jacobson KA, Fowler DH (2005) Activation of th1 and tc1 cell adenosine a2a receptors directly inhibits il-2 secretion in vitro and il-2-driven expansion in vivo. Blood 105(12):4707–4714

    Article  CAS  Google Scholar 

  146. Lappas CM, Day YJ, Marshall MA, Engelhard VH, Linden J (2006) Adenosine a2a receptor activation reduces hepatic ischemia reperfusion injury by inhibiting cd1d-dependent nkt cell activation. J Exp Med 203(12):2639–2648

    Article  CAS  Google Scholar 

  147. Miller JS, Cervenka T, Lund J, Okazaki IJ, Moss J (1999) Purine metabolites suppress proliferation of human nk cells through a lineage-specific purine receptor. J Immunol 162(12):7376–7382

    Article  CAS  Google Scholar 

  148. Lokshin A, Raskovalova T, Huang X, Zacharia LC, Jackson EK, Gorelik E (2006) Adenosine-mediated inhibition of the cytotoxic activity and cytokine production by activated natural killer cells. Cancer Res 66(15):7758–7765

    Article  CAS  Google Scholar 

  149. Sevigny CP, Li L, Awad AS, Huang L, McDuffie M, Linden J, Lobo PI, Okusa MD (2007) Activation of adenosine 2a receptors attenuates allograft rejection and alloantigen recognition. J Immunol 178(7):4240–4249

    Article  CAS  Google Scholar 

  150. Ohta A, Kini R, Ohta A, Subramanian M, Madasu M, Sitkovsky M (2012) 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

    Article  CAS  Google Scholar 

  151. Gerlo S, Verdood P, Hooghe-Peters EL, Kooijman RJC, Sciences ML (2005) Multiple camp-induced signaling cascades regulate prolactin expression in t cells. Cell Mol Life Sci 63(1):92

    Article  CAS  Google Scholar 

  152. Jimenez JL, Punzon C, Navarro J, Munoz-Fernandez MA, Fresno M (2001) Phosphodiesterase 4 inhibitors prevent cytokine secretion by t lymphocytes by inhibiting nuclear factor-kappab and nuclear factor of activated t cells activation. J Pharmacol Exp Ther 299(2):753–759

    CAS  Google Scholar 

  153. Su Y, Huang X, Raskovalova T, Zacharia L, Lokshin A, Jackson E, Gorelik EJCI (2008) Immunotherapy: cooperation of adenosine and prostaglandin e2 (pge2) in amplification of camp–pka signaling and immunosuppression. Cancer Immunol Immunother 57(11):1611–1623

    Article  CAS  Google Scholar 

  154. Raskovalova T, Lokshin A, Huang X, Su Y, Mandic M, Zarour HM, Jackson EK, Gorelik E (2007) 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(12):5949–5956

    Article  CAS  Google Scholar 

  155. Carey KD, Dillon TJ, Schmitt JM, Baird AM, Holdorf AD, Straus DB, Shaw AS, Stork PJS (2000) Cd28 and the tyrosine kinase lck stimulate mitogen-activated protein kinase activity in t cells via inhibition of the small g protein rap1. Mol Cell Biol 20(22):8409–8419

    Article  CAS  Google Scholar 

  156. Bivona TG, Wiener HH, Ahearn IM, Silletti J, Chiu VK, Philips MR (2004) Rap1 up-regulation and activation on plasma membrane regulates t cell adhesion. J Cell Biol 164(3):461–470

    Article  CAS  Google Scholar 

  157. Linnemann C, Schildberg FA, Schurich A, Diehl L, Hegenbarth SI, Endl E, Lacher S, Müller CE, Frey J, Simeoni L, Schraven B et al (2009) Adenosine regulates cd8 t-cell priming by inhibition of membrane-proximal t-cell receptor signalling. Immunology 128(1 Suppl):e728–e737

    Article  Google Scholar 

  158. Sorrentino C, Hossain F, Rodriguez PC, Sierra RA, Pannuti A, Osborne BA, Minter LM, Miele L, Morello S (2019) Adenosine a2a receptor stimulation inhibits tcr-induced notch1 activation in cd8+t-cells. Front Immunol 10:162–162

    Article  CAS  Google Scholar 

  159. Vigano S, Alatzoglou D, Irving M, Ménétrier-Caux C, Caux C, Romero P, Coukos G (2019) Targeting adenosine in cancer immunotherapy to enhance t-cell function. Front Immunol 10:925

    Article  CAS  Google Scholar 

  160. Mittal D, Young A, Stannard K, Yong M, Teng MWL, Allard B, Stagg J, Smyth MJ (2014) Antimetastatic effects of blocking pd-1 and the adenosine a2a receptor. Cancer Res 74(14):3652–3658

    Article  CAS  Google Scholar 

  161. Beavis PA, Milenkovski N, Henderson MA, John LB, Allard B, Loi S, Kershaw MH, Stagg J, Darcy PK (2015) Adenosine receptor 2a blockade increases the efficacy of anti-pd-1 through enhanced antitumor t-cell responses. Cancer Immunol Res 3(5):506–517

    Article  CAS  Google Scholar 

  162. Willingham SB, Ho PY, Hotson A, Hill C, Piccione EC, Hsieh J, Liu L, Buggy JJ, McCaffery I, Miller RA (2018) A2ar antagonism with cpi-444 induces antitumor responses and augments efficacy to anti-pd-(l)1 and anti-ctla-4 in preclinical models. Cancer Immunol Res 6(10):1136–1149

    Article  CAS  Google Scholar 

  163. Iannone R, Miele L, Maiolino P, Pinto A, Morello S (2014) Adenosine limits the therapeutic effectiveness of anti-ctla4 mab in a mouse melanoma model. Am J Cancer Res 4(2):172–181

    Google Scholar 

  164. Leone RD, Sun IM, Oh MH, Sun IH, Wen J, Englert J, Powell JD (2018) 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 Immunology Immunother CII 67(8):1271–1284

    Article  CAS  Google Scholar 

  165. Kjaergaard J, Hatfield S, Jones G, Ohta A, Sitkovsky M (2018) A(2a) adenosine receptor gene deletion or synthetic a(2a) antagonist liberate tumor-reactive cd8(+) t cells from tumor-induced immunosuppression. J Immunol 201(2):782–791

    Article  CAS  Google Scholar 

  166. Beavis PA, Henderson MA, Giuffrida L, Mills JK, Sek K, Cross RS, Davenport AJ, John LB, Mardiana S, Slaney CY, Johnstone RW et al (2017) Targeting the adenosine 2a receptor enhances chimeric antigen receptor t cell efficacy. J Clin Invest 127(3):929–941

    Article  Google Scholar 

  167. Nakatsukasa H, Tsukimoto M, Harada H, Kojima S (2011) Adenosine a2b receptor antagonist suppresses differentiation to regulatory t cells without suppressing activation of t cells. Biochem Biophys Res Commun 409(1):114–119

    Article  CAS  Google Scholar 

  168. Martinez RJ, Zhang N, Thomas SR, Nandiwada SL, Jenkins MK, Binstadt BA, Mueller DL (2012) Arthritogenic self-reactive cd4+ t cells acquire an fr4hicd73hi anergic state in the presence of foxp3+ regulatory t cells. J Immunol 188(1):170–181

    Article  CAS  Google Scholar 

  169. Jin D, Fan J, Wang L, Thompson LF, Liu A, Daniel BJ, Shin T, Curiel TJ, Zhang B (2010) Cd73 on tumor cells impairs antitumor t-cell responses: a novel mechanism of tumor-induced immune suppression. Cancer Res 70(6):2245–2255

    Article  CAS  Google Scholar 

  170. Stagg J, Divisekera U, Duret H, Sparwasser T, Teng MWL, Darcy PK, Smyth MJ (2011) Cd73-deficient mice have increased antitumor immunity and are resistant to experimental metastasis. Cancer Res 71(8):2892–2900

    Article  CAS  Google Scholar 

  171. Stagg J, Beavis PA, Divisekera U, Liu MC, Moller A, Darcy PK, Smyth MJ (2012) Cd73-deficient mice are resistant to carcinogenesis. Cancer Res 72(9):2190–2196

    Article  CAS  Google Scholar 

  172. Loi S, Pommey S, Haibe-Kains B, Beavis PA, Darcy PK, Smyth MJ, Stagg J (2013) Cd73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer. Proc Natl Acad Sci U S A 110(27):11091–11096

    Article  CAS  Google Scholar 

  173. Young A, Ngiow SF, Barkauskas DS, Sult E, Hay C, Blake SJ, Huang Q, Liu J, Takeda K, Teng MWL, Sachsenmeier K et al (2016) Co-inhibition of cd73 and a2ar adenosine signaling improves anti-tumor immune responses. Cancer Cell 30(3):391–403

    Article  CAS  Google Scholar 

  174. Zhang F, Li R, Yang Y, Shi C, Shen Y, Lu C, Chen Y, Zhou W, Lin A, Yu L, Zhang W et al (2019) Specific decrease in b-cell-derived extracellular vesicles enhances post-chemotherapeutic cd8(+) t cell responses. Immunity 50(3):738–750.e737

    Article  CAS  Google Scholar 

  175. Melet A, Song K, Bucur O, Jagani Z, Grassian AR, Khosravi-Far R (2008) Apoptotic pathways in tumor progression and therapy. Adv Exp Med Biol 615:47–79

    Article  CAS  Google Scholar 

  176. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  CAS  Google Scholar 

  177. Tait SW, Green DR (2010) Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11(9):621–632

    Article  CAS  Google Scholar 

  178. Wong RS (2011) Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res 30:87

    Article  CAS  Google Scholar 

  179. Saito M, Yaguchi T, Yasuda Y, Nakano T, Nishizaki T (2010) Adenosine suppresses cw2 human colonic cancer growth by inducing apoptosis via a(1) adenosine receptors. Cancer Lett 290(2):211–215

    Article  CAS  Google Scholar 

  180. Wen LT, Knowles AF (2003) Extracellular atp and adenosine induce cell apoptosis of human hepatoma li-7a cells via the a3 adenosine receptor. Br J Pharmacol 140(6):1009–1018

    Article  CAS  Google Scholar 

  181. Kim SG, Ravi G, Hoffmann C, Jung YJ, Kim M, Chen A, Jacobson KA (2002) P53-independent induction of fas and apoptosis in leukemic cells by an adenosine derivative, cl-ib-meca. Biochem Pharmacol 63(5):871–880

    Article  CAS  Google Scholar 

  182. Mlejnek P, Dolezel P, Kosztyu P (2012) P-glycoprotein mediates resistance to a3 adenosine receptor agonist 2-chloro-n6-(3-iodobenzyl)-adenosine-5′-n-methyluronamide in human leukemia cells. J Cell Physiol 227(2):676–685

    Article  CAS  Google Scholar 

  183. Cohen S, Stemmer SM, Zozulya G, Ochaion A, Patoka R, Barer F, Bar-Yehuda S, Rath-Wolfson L, Jacobson KA, Fishman P (2011) Cf102 an a3 adenosine receptor agonist mediates anti-tumor and anti-inflammatory effects in the liver. J Cell Physiol 226(9):2438–2447

    Article  CAS  Google Scholar 

  184. Yasuda Y, Saito M, Yamamura T, Yaguchi T, Nishizaki T (2009) Extracellular adenosine induces apoptosis in caco-2 human colonic cancer cells by activating caspase-9/−3 via a(2a) adenosine receptors. J Gastroenterol 44(1):56–65

    Article  CAS  Google Scholar 

  185. Otsuki T, Kanno T, Fujita Y, Tabata C, Fukuoka K, Nakano T, Gotoh A, Nishizaki T (2012) A3 adenosine receptor-mediated p53-dependent apoptosis in lu-65 human lung cancer cells. Cell Physiol Biochem 30(1):210–220

    Article  CAS  Google Scholar 

  186. Aghaei M, Panjehpour M, Karami-Tehrani F, Salami S (2011) Molecular mechanisms of a3 adenosine receptor-induced g1 cell cycle arrest and apoptosis in androgen-dependent and independent prostate cancer cell lines: involvement of intrinsic pathway. J Cancer Res Clin Oncol 137(10):1511–1523

    Article  CAS  Google Scholar 

  187. Yang D, Yaguchi T, Nakano T, Nishizaki T (2010) Adenosine-induced caspase-3 activation by tuning bcl-xl/diablo/iap expression in huh-7 human hepatoma cells. Cell Biol Toxicol 26(4):319–330

    Article  CAS  Google Scholar 

  188. Yang D, Yaguchi T, Nakano T, Nishizaki T (2011) Adenosine activates ampk to phosphorylate bcl-xl responsible for mitochondrial damage and diablo release in huh-7 cells. Cell Physiol Biochem 27(1):71–78

    Article  CAS  Google Scholar 

  189. Sai K, Yang D, Yamamoto H, Fujikawa H, Yamamoto S, Nagata T, Saito M, Yamamura T, Nishizaki T (2006) A(1) adenosine receptor signal and ampk involving caspase-9/−3 activation are responsible for adenosine-induced rcr-1 astrocytoma cell death. Neurotoxicology 27(4):458–467

    Article  CAS  Google Scholar 

  190. Broker LE, Kruyt FA, Giaccone G (2005) Cell death independent of caspases: a review. Clin Cancer Res 11(9):3155–3162

    Article  Google Scholar 

  191. Cande C, Cecconi F, Dessen P, Kroemer G (2002) Apoptosis-inducing factor (aif): key to the conserved caspase-independent pathways of cell death? J Cell Sci 115(Pt 24):4727–4734

    Article  CAS  Google Scholar 

  192. Kanno T, Gotoh A, Fujita Y, Nakano T, Nishizaki T (2012) A(3) adenosine receptor mediates apoptosis in 5637 human bladder cancer cells by g(q) protein/pkc-dependent aif upregulation. Cell Physiol Biochem 30(5):1159–1168

    Article  CAS  Google Scholar 

  193. Nagaya H, Gotoh A, Kanno T, Nishizaki T (2013) A3 adenosine receptor mediates apoptosis in in vitro rcc4-vhl human renal cancer cells by up-regulating amid expression. J Urol 189(1):321–328

    Article  CAS  Google Scholar 

  194. Kanno T, Nakano T, Fujita Y, Gotoh A, Nishizaki T (2012) Adenosine induces apoptosis in sbc-3 human lung cancer cells through a(3) adenosine receptor-dependent amid upregulation. Cell Physiol Biochem 30(3):666–677

    Article  CAS  Google Scholar 

  195. Wu M, Xu LG, Li X, Zhai Z, Shu HB (2002) Amid, an apoptosis-inducing factor-homologous mitochondrion-associated protein, induces caspase-independent apoptosis. J Biol Chem 277(28):25617–25623

    Article  CAS  Google Scholar 

  196. Tsuchiya A, Kanno T, Saito M, Miyoshi Y, Gotoh A, Nakano T, Nishizaki T (2012) Intracellularly transported adenosine induces apoptosis in [corrected] mcf-7 human breast cancer cells by accumulating amid in the nucleus. Cancer Lett 321(1):65–72

    Article  CAS  Google Scholar 

  197. Ciardiello F, Tortora G (2008) Egfr antagonists in cancer treatment. N Engl J Med 358(11):1160–1174

    Article  CAS  Google Scholar 

  198. Sadikovic B, Al-Romaih K, Squire JA, Zielenska M (2008) Cause and consequences of genetic and epigenetic alterations in human cancer. Curr Genomics 9(6):394–408

    Article  CAS  Google Scholar 

  199. Johnson DG, Walker CL (1999) Cyclins and cell cycle checkpoints. Annu Rev Pharmacol Toxicol 39:295–312

    Article  CAS  Google Scholar 

  200. Ohana G, Bar-Yehuda S, Barer F, Fishman P (2001) Differential effect of adenosine on tumor and normal cell growth: focus on the a3 adenosine receptor. J Cell Physiol 186(1):19–23

    Article  CAS  Google Scholar 

  201. Mirza A, Basso A, Black S, Malkowski M, Kwee L, Pachter JA, Lachowicz JE, Wang Y, Liu S (2005) Rna interference targeting of a1 receptor-overexpressing breast carcinoma cells leads to diminished rates of cell proliferation and induction of apoptosis. Cancer Biol Ther 4(12):1355–1360

    Article  CAS  Google Scholar 

  202. Lin Z, Yin P, Reierstad S, O’Halloran M, Coon VJ, Pearson EK, Mutlu GM, Bulun SE (2010) Adenosine a1 receptor, a target and regulator of estrogen receptoralpha action, mediates the proliferative effects of estradiol in breast cancer. Oncogene 29(8):1114–1122

    Article  CAS  Google Scholar 

  203. Etique N, Grillier-Vuissoz I, Lecomte J, Flament S (2009) Crosstalk between adenosine receptor (a2a isoform) and eralpha mediates ethanol action in mcf-7 breast cancer cells. Oncol Rep 21(4):977–981

    CAS  Google Scholar 

  204. Ma DF, Kondo T, Nakazawa T, Niu DF, Mochizuki K, Kawasaki T, Yamane T, Katoh R (2010) Hypoxia-inducible adenosine a2b receptor modulates proliferation of colon carcinoma cells. Hum Pathol 41(11):1550–1557

    Article  CAS  Google Scholar 

  205. Wei Q, Costanzi S, Balasubramanian R, Gao ZG, Jacobson KA (2013) A(2b) adenosine receptor blockade inhibits growth of prostate cancer cells. Purinergic Signal 9:271

    Article  CAS  Google Scholar 

  206. Panjehpour M, Karami-Tehrani F (2004) An adenosine analog (ib-meca) inhibits anchorage-dependent cell growth of various human breast cancer cell lines. Int J Biochem Cell Biol 36(8):1502–1509

    Article  CAS  Google Scholar 

  207. Merighi S, Mirandola P, Milani D, Varani K, Gessi S, Klotz KN, Leung E, Baraldi PG, Borea PA (2002) Adenosine receptors as mediators of both cell proliferation and cell death of cultured human melanoma cells. J Invest Dermatol 119(4):923–933

    Article  CAS  Google Scholar 

  208. Madi L, Bar-Yehuda S, Barer F, Ardon E, Ochaion A, Fishman P (2003) A3 adenosine receptor activation in melanoma cells: association between receptor fate and tumor growth inhibition. J Biol Chem 278(43):42121–42130

    Article  CAS  Google Scholar 

  209. Merighi S, Benini A, Mirandola P, Gessi S, Varani K, Leung E, Maclennan S, Borea PA (2005) A3 adenosine receptor activation inhibits cell proliferation via phosphatidylinositol 3-kinase/akt-dependent inhibition of the extracellular signal-regulated kinase 1/2 phosphorylation in a375 human melanoma cells. J Biol Chem 280(20):19516–19526

    Article  CAS  Google Scholar 

  210. Fishman P, Bar-Yehuda S, Ohana G, Barer F, Ochaion A, Erlanger A, Madi L (2004) An agonist to the a3 adenosine receptor inhibits colon carcinoma growth in mice via modulation of gsk-3 beta and nf-kappa b. Oncogene 23(14):2465–2471

    Article  CAS  Google Scholar 

  211. Fishman P, Bar-Yehuda S, Ohana G, Pathak S, Wasserman L, Barer F, Multani AS (2000) Adenosine acts as an inhibitor of lymphoma cell growth: a major role for the a3 adenosine receptor. Eur J Cancer (Oxford, England : 1990) 36(11):1452–1458

    Article  CAS  Google Scholar 

  212. Ohana G, Bar-Yehuda S, Arich A, Madi L, Dreznick Z, Rath-Wolfson L, Silberman D, Slosman G, Fishman P (2003) Inhibition of primary colon carcinoma growth and liver metastasis by the a3 adenosine receptor agonist cf101. Br J Cancer 89(8):1552–1558

    Article  CAS  Google Scholar 

  213. Panjehpour M, Karami-Tehrani F (2007) Adenosine modulates cell growth in the human breast cancer cells via adenosine receptors. Oncol Res 16(12):575–585

    Article  CAS  Google Scholar 

  214. Bar-Yehuda S, Barer F, Volfsson L, Fishman P (2001) Resistance of muscle to tumor metastases: a role for a3 adenosine receptor agonists. Neoplasia (New York, NY) 3(2):125–131

    Article  CAS  Google Scholar 

  215. Fishman P, Bar-Yehuda S, Barer F, Madi L, Multani AS, Pathak S (2001) The a3 adenosine receptor as a new target for cancer therapy and chemoprotection. Exp Cell Res 269(2):230–236

    Article  CAS  Google Scholar 

  216. Fishman P, Madi L, Bar-Yehuda S, Barer F, Del Valle L, Khalili K (2002) Evidence for involvement of wnt signaling pathway in ib-meca mediated suppression of melanoma cells. Oncogene 21(25):4060–4064

    Article  CAS  Google Scholar 

  217. Lu J, Pierron A, Ravid K (2003) An adenosine analogue, ib-meca, down-regulates estrogen receptor alpha and suppresses human breast cancer cell proliferation. Cancer Res 63(19):6413–6423

    CAS  Google Scholar 

  218. Chung H, Jung JY, Cho SD, Hong KA, Kim HJ, Shin DH, Kim H, Kim HO, Shin DH, Lee HW, Jeong LS et al (2006) The antitumor effect of lj-529, a novel agonist to a3 adenosine receptor, in both estrogen receptor-positive and estrogen receptor-negative human breast cancers. Mol Cancer Ther 5(3):685–692

    Article  CAS  Google Scholar 

  219. Morello S, Petrella A, Festa M, Popolo A, Monaco M, Vuttariello E, Chiappetta G, Parente L, Pinto A (2008) Cl-ib-meca inhibits human thyroid cancer cell proliferation independently of a3 adenosine receptor activation. Cancer Biol Ther 7(2):278–284

    Article  CAS  Google Scholar 

  220. Chiang AC, Massague J (2008) Molecular basis of metastasis. N Engl J Med 359(26):2814–2823

    Article  CAS  Google Scholar 

  221. Spano D, Heck C, De Antonellis P, Christofori G, Zollo M (2012) Molecular networks that regulate cancer metastasis. Semin Cancer Biol 22(3):234–249

    Article  CAS  Google Scholar 

  222. Kunzli BM, Bernlochner MI, Rath S, Kaser S, Csizmadia E, Enjyoji K, Cowan P, d’Apice A, Dwyer K, Rosenberg R, Perren A et al (2011) Impact of cd39 and purinergic signalling on the growth and metastasis of colorectal cancer. Purinergic Signal 7(2):231–241

    Article  CAS  Google Scholar 

  223. Arab S, Hadjati J (2019) Adenosine blockage in tumor microenvironment and improvement of cancer immunotherapy. Immune Netw 19(4):e23

    Article  Google Scholar 

  224. Leone RD, Emens LA (2018) Targeting adenosine for cancer immunotherapy. J Immunother Cancer 6(1):57

    Article  Google Scholar 

  225. Zhou P, Zhi X, Zhou T, Chen S, Li X, Wang L, Yin L, Shao Z, Ou Z (2007) Overexpression of ecto-5′-nucleotidase (cd73) promotes t-47d human breast cancer cells invasion and adhesion to extracellular matrix. Cancer Biol Ther 6(3):426–431

    Article  CAS  Google Scholar 

  226. Wang L, Zhou X, Zhou T, Ma D, Chen S, Zhi X, Yin L, Shao Z, Ou Z, Zhou P (2008) Ecto-5′-nucleotidase promotes invasion, migration and adhesion of human breast cancer cells. J Cancer Res Clin Oncol 134(3):365–372

    Article  CAS  Google Scholar 

  227. Cappellari AR, Rockenbach L, Dietrich F, Clarimundo V, Glaser T, Braganhol E, Abujamra AL, Roesler R, Ulrich H, Battastini AM (2012) Characterization of ectonucleotidases in human medulloblastoma cell lines: Ecto-5’nt/cd73 in metastasis as potential prognostic factor. PLoS One 7(10):e47468

    Article  CAS  Google Scholar 

  228. Zhi X, Chen S, Zhou P, Shao Z, Wang L, Ou Z, Yin L (2007) Rna interference of ecto-5′-nucleotidase (cd73) inhibits human breast cancer cell growth and invasion. Clin Exp Metastasis 24(6):439–448

    Article  CAS  Google Scholar 

  229. Desmet CJ, Gallenne T, Prieur A, Reyal F, Visser NL, Wittner BS, Smit MA, Geiger TR, Laoukili J, Iskit S, Rodenko B et al (2013) Identification of a pharmacologically tractable fra-1/adora2b axis promoting breast cancer metastasis. Proc Natl Acad Sci U S A 110(13):5139–5144

    Article  CAS  Google Scholar 

  230. Ntantie E, Gonyo P, Lorimer EL, Hauser AD, Schuld N, McAllister D, Kalyanaraman B, Dwinell MB, Auchampach JA, Williams CL (2013) An adenosine-mediated signaling pathway suppresses prenylation of the gtpase rap1b and promotes cell scattering. Sci Signal 6(277):ra39

    Article  CAS  Google Scholar 

  231. Beavis PA, Divisekera U, Paget C, Chow MT, John LB, Devaud C, Dwyer K, Stagg J, Smyth MJ, Darcy PK (2013) Blockade of a2a receptors potently suppresses the metastasis of cd73+ tumors. Proc Natl Acad Sci U S A 110(36):14711–14716

    Article  CAS  Google Scholar 

  232. Mao L, Fan TF, Wu L, Yu GT, Deng WW, Chen L, Bu LL, Ma SR, Liu B, Bian Y, Kulkarni AB et al (2017) Selective blockade of b7-h3 enhances antitumour immune activity by reducing immature myeloid cells in head and neck squamous cell carcinoma. J Cell Mol Med 21(9):2199–2210

    Article  CAS  Google Scholar 

  233. Shi L, Wu Z, Miao J, Du S, Ai S, Xu E, Feng M, Song J, Guan W (2019) Adenosine interaction with adenosine receptor a2a promotes gastric cancer metastasis by enhancing pi3k-akt-mtor signaling. Mol Biol Cell 30(19):2527–2534

    Article  CAS  Google Scholar 

  234. Alderton GK (2012) Metastasis. Exosomes drive premetastatic niche formation. Nat Rev Cancer 12(7):447

    Article  CAS  Google Scholar 

  235. Clayton A, Al-Taei S, Webber J, Mason MD, Tabi Z (2011) Cancer exosomes express cd39 and cd73, which suppress t cells through adenosine production. J Immunol 187(2):676–683

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Luca Antonioli

  2. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Matteo Fornai, Vanessa D’Antongiovanni & Corrado Blandizzi

  3. Department of Pharmacy, University of Pisa, Pisa, Italy

    Carolina Pellegrini

  4. Department of Pharmacy, University of Salerno, Fisciano, Italy

    Roberta Turiello & Silvana Morello

  5. PhD Program in Drug discovery and Development, Department of Pharmacy, University of Salerno, Fisciano, Italy

    Roberta Turiello

  6. Department of Anesthesiology, Columbia University, New York, NY, USA

    György Haskó

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  1. Luca Antonioli
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Correspondence to Luca Antonioli .

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  1. Department of Radiology, Columbia University Medical Center, New York, NY, USA, Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

    Alexander Birbrair

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Antonioli, L. et al. (2021). Adenosine Signaling in the Tumor Microenvironment. In: Birbrair, A. (eds) Tumor Microenvironment. Advances in Experimental Medicine and Biology, vol 1270. Springer, Cham. https://doi.org/10.1007/978-3-030-47189-7_9

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