Skip to main content
SpringerLink
Log in

The Hypoxia-adenosinergic Immunosuppression and Redirection of Immune Response in Tumor Microenvironment

  • Chapter
  • First Online:
Tumor-Induced Immune Suppression

Abstract

In this chapter, we will focus on physiological regulators of activated immune cells in cancerous tissue microenvironments. This consideration started when we were contemplating the molecular mechanism that would be responsible for the so-called Hellstrom Paradox. Indeed, it was not explained why cancer patients often have tumor-recognizing effector T cells without having tumor rejection. The latest great advances in identification of various immunological negative regulators of immune response still left room for tumor defense by physiological inhibitors of antitumor T and natural killer (NK) cells. We started by assuming that cancerous tissues could be misguidedly protected by the same mechanism, which saves lives by protecting vital tissues from collateral damage by overactive immune cells during the antipathogen immune response. In our search for a mechanism that protects tissues from collateral damage, we first focused on intracellular cyclic adenosine monophosphate (cAMP) which was long known to be immunosuppressive. It was important to identify which of the many Gs protein-coupled receptors is actually physiologically responsible for inhibition of immune response in tumor microenvironment. Levels of extracellular adenosine are high in inflamed and cancerous tissues corresponding to local hypoxia. A2A and A2B subtypes of adenosine receptor, which are coupled to cAMP-elevating Gs protein, are predominantly expressed in immune cells. Indeed, extracellular adenosine endogenously generated by degradation of adenosine triphosphate (ATP) could suppress immune response and immunoregulation by adenosine was notable in tumor microenvironment. Blockade of the hypoxia-adenosinergic immunosuppression may be a promising approach to eradicate cancer, especially when it is combined with adoptive immunotherapy or cancer vaccine.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Caldwell CC, Kojima H, Lukashev D, Armstrong J, Farber M, Apasov SG, Sitkovsky MV (2001) Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions. J Immunol 167(11):6140–6149

    CAS  PubMed  Google Scholar 

  2. Braun RD, Lanzen JL, Snyder SA, Dewhirst MW (2001) Comparison of tumor and normal tissue oxygen tension measurements using OxyLite or microelectrodes in rodents. Am J Physiol Heart Circ Physiol 280(6):H2533–2544

    CAS  PubMed  Google Scholar 

  3. Karhausen J, Haase VH, Colgan SP (2005) Inflammatory hypoxia: role of hypoxia-inducible factor. Cell Cycle 4(2):256–258

    CAS  PubMed  Google Scholar 

  4. Kominsky DJ, Campbell EL, Colgan SP (2010) Metabolic shifts in immunity and inflammation. J Immunol 184(8):4062–4068. doi:10.4049/jimmunol.0903002

    CAS  PubMed  Google Scholar 

  5. Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26(2):225–239. doi:10.1007/s10555-007-9055-1

    CAS  PubMed  Google Scholar 

  6. Dewhirst MW, Cao Y, Moeller B (2008) Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer 8(6):425–437. doi:10.1038/nrc2397

    CAS  PubMed  Google Scholar 

  7. Minchinton AI, Tannock IF (2006) Drug penetration in solid tumours. Nat Rev Cancer 6(8):583–592. doi:10.1038/nrc1893

    CAS  PubMed  Google Scholar 

  8. Finn OJ (2008) Cancer immunology. N Eng J Med 358(25):2704–2715. doi:10.1056/NEJMra072739

    CAS  Google Scholar 

  9. Mellor AL, Munn DH (2008) Creating immune privilege: active local suppression that benefits friends, but protects foes. Nature reviews. Immunology 8(1):74–80. doi:10.1038/nri2233

    CAS  PubMed  Google Scholar 

  10. 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. doi:10.1158/1078-0432.CCR-08-0229

    PubMed  Google Scholar 

  11. Loeffler DA, Juneau PL, Masserant S (1992) Influence of tumour physico-chemical conditions on interleukin-2-stimulated lymphocyte proliferation. Br J Cancer 66(4):619–622

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Naldini A, Carraro F, Silvestri S, Bocci V (1997) Hypoxia affects cytokine production and proliferative responses by human peripheral mononuclear cells. J Cell Physiol 173(3):335–342. doi:10.1002/(SICI)1097-4652(199712)173:3<335::AID-JCP5>3.0.CO;2-O

    CAS  PubMed  Google Scholar 

  13. Atkuri KR, Herzenberg LA, Herzenberg LA (2005) Culturing at atmospheric oxygen levels impacts lymphocyte function. Proc Natl Acad Sci U S A 102(10):3756–3759. doi:10.1073/pnas.0409910102

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Neumann AK, Yang J, Biju MP, Joseph SK, Johnson RS, Haase VH, Freedman BD, Turka LA (2005) Hypoxia inducible factor 1 alpha regulates T cell receptor signal transduction. Proc Natl Acad Sci U S A 102(47):17071–17076. doi:10.1073/pnas.0506070102

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Ohta A, Diwanji R, Kini R, Subramanian M, Ohta A, Sitkovsky M (2011) In vivo T cell activation in lymphoid tissues is inhibited in the oxygen-poor microenvironment. Front Immunol 2:27. doi:10.3389/fimmu.2011.00027

    PubMed Central  PubMed  Google Scholar 

  16. Semenza GL (2007) Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1. Biochem J 405(1):1–9. doi:10.1042/BJ20070389

    CAS  PubMed  Google Scholar 

  17. Majmundar AJ, Wong WJ, Simon MC (2010) Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell 40(2):294–309. doi:10.1016/j.molcel.2010.09.022

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Lukashev D, Klebanov B, Kojima H, Grinberg A, Ohta A, Berenfeld L, Wenger RH, Ohta A, Sitkovsky M (2006) Cutting edge: hypoxia-inducible factor 1alpha and its activation-inducible short isoform I.1 negatively regulate functions of CD4+ and CD8+ T lymphocytes. J Immunol 177(8):4962–4965

    CAS  PubMed  Google Scholar 

  19. Guo J, Lu W, Shimoda LA, Semenza GL, Georas SN (2009) Enhanced interferon-gamma gene expression in T Cells and reduced ovalbumin-dependent lung eosinophilia in hypoxia-inducible factor-1-alpha-deficient mice. Int Arch Allergy Immunol 149(2):98–102. doi:10.1159/000189191

    CAS  PubMed  Google Scholar 

  20. 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  PubMed  Google Scholar 

  21. Ohta A, Gorelik E, Prasad SJ, Ronchese F, Lukashev D, Wong MK, Huang X, Caldwell S, Liu K, Smith P, Chen JF, Jackson EK, Apasov S, Abrams S, Sitkovsky M (2006) A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci U S A 103(35):13132–13137. doi:10.1073/pnas.0605251103

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Colgan SP, Eltzschig HK, Eckle T, Thompson LF (2006) Physiological roles for ecto-5’-nucleotidase (CD73). Purinergic Signal 2(2):351–360. doi:10.1007/s11302-005-5302-5

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Volmer JB, Thompson LF, Blackburn MR (2006) Ecto-5’-nucleotidase (CD73)-mediated adenosine production is tissue protective in a model of bleomycin-induced lung injury. J Immunol 176(7):4449–4458

    CAS  PubMed  Google Scholar 

  24. Grenz A, Zhang H, Weingart J, von Wietersheim S, Eckle T, Schnermann J, Kohle C, Kloor D, Gleiter CH, Vallon V, Eltzschig HK, Osswald H (2007) Lack of effect of extracellular adenosine generation and signaling on renal erythropoietin secretion during hypoxia. Am J Physiol Renal Physio 293(5):F1501–1511. doi:10.1152/ajprenal.00243.2007

    CAS  Google Scholar 

  25. Resta R, Hooker SW, Laurent AB, Jamshedur Rahman SM, Franklin M, Knudsen TB, Nadon NL, Thompson LF (1997) Insights into thymic purine metabolism and adenosine deaminase deficiency revealed by transgenic mice overexpressing ecto-5’-nucleotidase (CD73). J Clin Invest 99(4):676–683. doi:10.1172/JCI119211

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Tofovic SP, Zacharia L, Carcillo JA, Jackson EK (2001) Inhibition of adenosine deaminase attenuates endotoxin-induced release of cytokines in vivo in rats. Shock 16(3):196–202

    CAS  PubMed  Google Scholar 

  27. Jarvis MF, Yu H, McGaraughty S, Wismer CT, Mikusa J, Zhu C, Chu K, Kohlhaas K, Cowart M, Lee CH, Stewart AO, Cox BF, Polakowski J, Kowaluk EA (2002) Analgesic and anti-inflammatory effects of A-286501, a novel orally active adenosine kinase inhibitor. Pain 96(1–2):107–118

    CAS  PubMed  Google Scholar 

  28. Laghi-Pasini F, Guideri F, Petersen C, Lazzerini PE, Sicari R, Capecchi PL, Picano E (2003) Blunted increase in plasma adenosine levels following dipyridamole stress in dilated cardiomyopathy patients. J Internal Med 254(6):591–596

    CAS  PubMed  Google Scholar 

  29. Driver AG, Kukoly CA, Ali S, Mustafa SJ (1993) Adenosine in bronchoalveolar lavage fluid in asthma. Am Rev Respir Dis 148(1):91–97. doi:10.1164/ajrccm/148.1.91

    CAS  PubMed  Google Scholar 

  30. Nishiyama A, Miura K, Miyatake A, Fujisawa Y, Yue W, Fukui T, Kimura S, Abe Y (1999) Renal interstitial concentration of adenosine during endotoxin shock. Eur J Pharmacol 385(2–3):209–216

    CAS  PubMed  Google Scholar 

  31. Martin C, Leone M, Viviand X, Ayem ML, Guieu R (2000) High adenosine plasma concentration as a prognostic index for outcome in patients with septic shock. Crit Care Med 28(9):3198–3202

    CAS  PubMed  Google Scholar 

  32. Thiel M, Chouker A, Ohta A, Jackson E, Caldwell C, Smith P, Lukashev D, Bittmann I, Sitkovsky MV (2005) Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung injury. PLoS Biol 3(6):e174. doi:10.1371/journal.pbio.0030174

    PubMed Central  PubMed  Google Scholar 

  33. Lennon PF, Taylor CT, Stahl GL, Colgan SP (1998) 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

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Mizumoto N, Kumamoto T, Robson SC, Sevigny J, Matsue H, Enjyoji K, Takashima A (2002) CD39 is the dominant Langerhans cell-associated ecto-NTPDase: modulatory roles in inflammation and immune responsiveness. Nat Med 8(4):358–365. doi:10.1038/nm0402-358

    CAS  PubMed  Google Scholar 

  35. Synnestvedt K, Furuta GT, Comerford KM, Louis N, Karhausen J, Eltzschig HK, Hansen KR, Thompson LF, Colgan SP (2002) Ecto-5’-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J Clin Invest 110(7):993–1002. doi:10.1172/JCI15337

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Deaglio S, Robson SC (2011) Ectonucleotidases as regulators of purinergic signaling in thrombosis, inflammation, and immunity. Adv Pharmacol 61:301–332. doi:10.1016/B978-0-12-385526-8.00010-2

    CAS  PubMed  Google Scholar 

  37. Decking UK, Schlieper G, Kroll K, Schrader J (1997) Hypoxia-induced inhibition of adenosine kinase potentiates cardiac adenosine release. Circ Res 81(2):154–164

    CAS  PubMed  Google Scholar 

  38. Kobayashi S, Zimmermann H, Millhorn DE (2000) Chronic hypoxia enhances adenosine release in rat PC12 cells by altering adenosine metabolism and membrane transport. J Neurochem 74(2):621–632

    CAS  PubMed  Google Scholar 

  39. Morote-Garcia JC, Rosenberger P, Kuhlicke J, Eltzschig HK (2008) HIF-1-dependent repression of adenosine kinase attenuates hypoxia-induced vascular leak. Blood 111(12):5571–5580. doi:10.1182/blood-2007-11-126763

    CAS  PubMed  Google Scholar 

  40. Chouker A, Thiel M, Lukashev D, Ward JM, Kaufmann I, Apasov S, Sitkovsky MV, Ohta A (2008) Critical role of hypoxia and A2A adenosine receptors in liver tissue-protecting physiological anti-inflammatory pathway. Mol Med 14(3–4):116–123. doi:10.2119/2007-00075.Chouker

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Ujhazy P, Berleth ES, Pietkiewicz JM, Kitano H, Skaar JR, Ehrke MJ, Mihich E (1996) Evidence for the involvement of ecto-5’-nucleotidase (CD73) in drug resistance. Int J Cancer (Journal international du cancer) 68(4):493–500. doi:10.1002/(SICI)1097-0215(19961115)68:4<493::AID-IJC15>3.0.CO;2–6

    CAS  Google Scholar 

  42. 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. doi:10.1158/0008-5472.CAN-09-3109

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Hausler SF, Montalban del Barrio I, Strohschein J, Anoop Chandran P, Engel JB, Honig A, Ossadnik M, Horn E, Fischer B, Krockenberger M, Heuer S, Seida AA, Junker M, Kneitz H, Kloor D, Klotz KN, Dietl J, Wischhusen J (2011) 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. doi:10.1007/s00262-011-1040-4

    PubMed  Google Scholar 

  44. Serra S, Horenstein AL, Vaisitti T, Brusa D, Rossi D, Laurenti L, D’Arena G, Coscia M, Tripodo C, Inghirami G, Robson SC, Gaidano G, Malavasi F, Deaglio S (2011) CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death. Blood 118(23):6141–6152. doi:10.1182/blood-2011-08-374728

    CAS  PubMed  Google Scholar 

  45. Wolberg G, Zimmerman TP, Hiemstra K, Winston M, Chu LC (1975) Adenosine inhibition of lymphocyte-mediated cytolysis: possible role of cyclic adenosine monophosphate. Science 187(4180):957–959

    CAS  PubMed  Google Scholar 

  46. Zenser TV (1975) Formation of adenosine 3’,5’-monophosphate from adenosine in mouse thymocytes. Biochimica et biophysica acta 404(2):202–213

    CAS  PubMed  Google Scholar 

  47. Nordeen SK, Young DA (1976) Glucocorticoid action on rat thymic lymphocytes. Experiments utilizing adenosine to support cellular metabolism lead to a reassessment of catabolic hormone actions. J Biol Chem 251(23):7295–7303

    CAS  PubMed  Google Scholar 

  48. Birch RE, Polmar SH (1982) Pharmacological modification of immunoregulatory T lymphocytes. I. Effect of adenosine, H1 and H2 histamine agonists upon T lymphocyte regulation of B lymphocyte differentiation in vitro. Clin Exp Immunol 48(1):218–230

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Mandler R, Birch RE, Polmar SH, Kammer GM, Rudolph SA (1982) Abnormal adenosine-induced immunosuppression and cAMP metabolism in T lymphocytes of patients with systemic lupus erythematosus. Proc Natl Acad Sci U S A 79(23):7542–7546

    CAS  PubMed Central  PubMed  Google Scholar 

  50. DosReis GA, Nobrega AF, de Carvalho RP (1986) Purinergic modulation of T-lymphocyte activation: differential susceptibility of distinct activation steps and correlation with intracellular 3’,5’-cyclic adenosine monophosphate accumulation. Cell Immunol 101(1):213–231

    CAS  PubMed  Google Scholar 

  51. Gilbert KM, Hoffmann MK (1985) cAMP is an essential signal in the induction of antibody production by B cells but inhibits helper function of T cells. J Immunol 135(3):2084–2089

    CAS  PubMed  Google Scholar 

  52. Takayama H, Trenn G, Sitkovsky MV (1988) Locus of inhibitory action of cAMP-dependent protein kinase in the antigen receptor-triggered cytotoxic T lymphocyte activation pathway. J Biol Chem 263(5):2330–2336

    CAS  PubMed  Google Scholar 

  53. van Calker D, Muller M, Hamprecht B (1979) Adenosine regulates via two different types of receptors, the accumulation of cyclic AMP in cultured brain cells. J Neurochem 33(5):999–1005

    Google Scholar 

  54. Olsson RA, Pearson JD (1990) Cardiovascular purinoceptors. Physiol Rev 70(3):761–845

    CAS  PubMed  Google Scholar 

  55. Fredholm BB, AP IJ, Jacobson KA, Klotz KN, Linden J (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53(4):527–552

    CAS  PubMed  Google Scholar 

  56. Fredholm BB, AP IJ, Jacobson KA, Linden J, Muller CE (2011) International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors–an update. Pharmacol Rev 63(1):1–34. doi:10.1124/pr.110.003285

    CAS  PubMed  Google Scholar 

  57. Koshiba M, Kojima H, Huang S, Apasov S, Sitkovsky MV (1997) Memory of extracellular adenosine A2A purinergic receptor-mediated signaling in murine T cells. J Biol Chem 272(41):25881–25889

    CAS  PubMed  Google Scholar 

  58. Lukashev DE, Smith PT, Caldwell CC, Ohta A, Apasov SG, Sitkovsky MV (2003) Analysis of A2a receptor-deficient mice reveals no significant compensatory increases in the expression of A2b, A1, and A3 adenosine receptors in lymphoid organs. Biochem Pharmacol 65(12):2081–2090

    CAS  PubMed  Google Scholar 

  59. Huang S, Apasov S, Koshiba M, Sitkovsky M (1997) Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood 90(4):1600–1610

    CAS  PubMed  Google Scholar 

  60. Lappas CM, Rieger JM, Linden J (2005) A2A adenosine receptor induction inhibits IFN-gamma production in murine CD4+ T cells. J Immunol 174(2):1073–1080

    CAS  PubMed  Google Scholar 

  61. 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. doi:10.1182/blood-2007-03-081646

    CAS  PubMed  Google Scholar 

  62. Ohta A, Ohta A, Madasu M, Kini R, Subramanian M, Goel N, Sitkovsky M (2009) A2A adenosine receptor may allow expansion of T cells lacking effector functions in extracellular adenosine-rich microenvironments. J Immunol 183(9):5487–5493. doi:10.4049/jimmunol.0901247

    CAS  PubMed  Google Scholar 

  63. Koshiba M, Rosin DL, Hayashi N, Linden J, Sitkovsky MV (1999) Patterns of A2A extracellular adenosine receptor expression in different functional subsets of human peripheral T cells. Flow cytometry studies with anti-A2A receptor monoclonal antibodies. Mol Pharmacol 55(3):614–624

    CAS  PubMed  Google Scholar 

  64. 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. doi:10.1158/0008-5472.CAN-06-4249

    CAS  PubMed  Google Scholar 

  65. 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

    CAS  PubMed  Google Scholar 

  66. Linnemann C, Schildberg FA, Schurich A, Diehl L, Hegenbarth SI, Endl E, Lacher S, Muller CE, Frey J, Simeoni L, Schraven B, Stabenow D, Knolle PA (2009) Adenosine regulates CD8 T-cell priming by inhibition of membrane-proximal T-cell receptor signalling. Immunology 128(1 Suppl):e728–737. doi:10.1111/j.1365-2567.2009.03075.x

    PubMed  Google Scholar 

  67. Vang T, Torgersen KM, Sundvold V, Saxena M, Levy FO, Skalhegg BS, Hansson V, Mustelin T, Tasken K (2001) Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor. J Exp Med 193(4):497–507

    CAS  PubMed Central  PubMed  Google Scholar 

  68. 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. doi:10.1096/fj.08-107458

    CAS  PubMed  Google Scholar 

  69. Hasko G, Kuhel DG, Chen JF, Schwarzschild MA, Deitch EA, Mabley JG, Marton A, Szabo C (2000) Adenosine inhibits IL-12 and TNF-[alpha] production via adenosine A2a receptor-dependent and independent mechanisms. FASEB J 14(13):2065–2074. doi:10.1096/fj.99-0508com

    CAS  PubMed  Google Scholar 

  70. 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. doi:10.1182/blood-2002-07-2113

    CAS  PubMed  Google Scholar 

  71. Heijink IH, Vellenga E, Borger P, Postma DS, Monchy JG, Kauffman HF (2003) Polarized Th1 and Th2 cells are less responsive to negative feedback by receptors coupled to the AC/cAMP system compared to freshly isolated T cells. Brit J Pharmacol 138(8):1441–1450. doi:10.1038/sj.bjp.0705193

    CAS  Google Scholar 

  72. Ohta A, Kjaergaard J, Sharma S, Mohsin M, Goel N, Madasu M, Fradkov E, Ohta A, Sitkovsky M (2009) In vitro induction of T cells that are resistant to A2 adenosine receptor-mediated immunosuppression. Brit J Pharmacol 156(2):297–306. doi:10.1111/j.1476-5381.2008.00019.x

    CAS  Google Scholar 

  73. Rudensky AY (2011) Regulatory T cells and Foxp3. Immunol Rev 241(1):260–268. doi:10.1111/j.1600-065X.2011.01018.x

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Sakaguchi S (2011) Regulatory T cells: history and perspective. Method Mol Biol 707:3–17. doi:10.1007/978-1-61737-979-6_1

    CAS  Google Scholar 

  75. Sitkovsky MV (2009) T regulatory cells: hypoxia-adenosinergic suppression and re-direction of the immune response. Trends Immunol 30(3):102–108. doi:10.1016/j.it.2008.12.002

    CAS  PubMed  Google Scholar 

  76. 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. doi:10.3389/fimmu.2012.00190

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322(5899):271–275. doi:10.1126/science.1160062

    CAS  PubMed  Google Scholar 

  78. Kinsey GR, Huang L, Jaworska K, Khutsishvili K, Becker DA, Ye H, Lobo PI, Okusa MD (2012) Autocrine adenosine signaling promotes regulatory T cell-mediated renal protection. J Am Soc Nephrol 23(9):1528–1537. doi:10.1681/ASN.2012010070

    CAS  PubMed  Google Scholar 

  79. Han KL, Thomas SV, Koontz SM, Changpriroa CM, Ha SK, Malech HL, Kang EM (2013) Adenosine A(2)A receptor agonist-mediated increase in donor-derived regulatory T cells suppresses development of graft-versus-host disease. J Immunol 190(1):458–468. doi:10.4049/jimmunol.1201325

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Ehrentraut H, Westrich JA, Eltzschig HK, Clambey ET (2012) Adora2b adenosine receptor engagement enhances regulatory T cell abundance during endotoxin-induced pulmonary inflammation. PloS One 7(2):e32416. doi:10.1371/journal.pone.0032416

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Ben-Shoshan J, Maysel-Auslender S, Mor A, Keren G, George J (2008) Hypoxia controls CD4+ CD25+ regulatory T-cell homeostasis via hypoxia-inducible factor-1alpha. Eur J Immunol 38(9):2412–2418. doi:10.1002/eji.200838318

    CAS  PubMed  Google Scholar 

  82. Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL, Jedlicka P, de Zoeten EF, Cambier JC, Stenmark KR, Colgan SP, Eltzschig HK (2012) Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci U S A 109(41):E2784–2793. doi:10.1073/pnas.1202366109

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen HR, Luo W, Zeller K, Shimoda L, Topalian SL, Semenza GL, Dang CV, Pardoll DM, Pan F (2011) Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 146(5):772–784. doi:10.1016/j.cell.2011.07.033

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H (2011) HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208(7):1367–1376. doi:10.1084/jem.20110278

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Kobie JJ, Shah PR, Yang L, Rebhahn JA, Fowell DJ, Mosmann TR (2006) T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5’-adenosine monophosphate to adenosine. J Immunol 177(10):6780–6786

    CAS  PubMed  Google Scholar 

  86. Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, Kuchroo VK, Strom TB, Robson SC (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204(6):1257–1265. doi:10.1084/jem.20062512

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Mandapathil M, Szczepanski MJ, Szajnik M, Ren J, Jackson EK, Johnson JT, Gorelik E, Lang S, Whiteside TL (2010) Adenosine and prostaglandin E2 cooperate in the suppression of immune responses mediated by adaptive regulatory T cells. J Biol Chem 285(36):27571–27580. doi:10.1074/jbc.M110.127100

    CAS  PubMed  Google Scholar 

  88. Naganuma M, Wiznerowicz EB, Lappas CM, Linden J, Worthington MT, Ernst PB (2006) Cutting edge: critical role for A2A adenosine receptors in the T cell-mediated regulation of colitis. J Immunol 177(5):2765–2769

    CAS  PubMed  Google Scholar 

  89. Nagaraj S, Gabrilovich DI (2008) Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res 68(8):2561–2563. doi:10.1158/0008-5472.CAN-07-6229

    CAS  PubMed  Google Scholar 

  90. 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. doi:10.4049/jimmunol.1101225

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng P, Cho HI, Celis E, Quiceno DG, Padhya T, McCaffrey TV, McCaffrey JC, Gabrilovich DI (2010) HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med 207(11):2439–2453. doi:10.1084/jem.20100587

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Ben Addi A, Lefort A, Hua X, Libert F, Communi D, Ledent C, Macours P, Tilley SL, Boeynaems JM, Robaye B (2008) Modulation of murine dendritic cell function by adenine nucleotides and adenosine: involvement of the A(2B) receptor. Eur J Immunol 38(6):1610–1620. doi:10.1002/eji.200737781

    CAS  PubMed  Google Scholar 

  93. 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. doi:10.1182/blood-2008-02-136325

    CAS  PubMed  Google Scholar 

  94. Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32(5):593–604. doi:10.1016/j.immuni.2010.05.007

    CAS  PubMed  Google Scholar 

  95. Leibovich SJ, Chen JF, Pinhal-Enfield G, Belem PC, Elson G, Rosania A, Ramanathan M, Montesinos C, Jacobson M, Schwarzschild MA, Fink JS, Cronstein B (2002) Synergistic up-regulation of vascular endothelial growth factor expression in murine macrophages by adenosine A(2A) receptor agonists and endotoxin. Am J Pathol 160 (6):2231–2244. doi:10.1016/S0002-9440(10)61170-4

    CAS  PubMed  Google Scholar 

  96. 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. doi:10.1091/mbc.E06-07-0596

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Mancino A, Schioppa T, Larghi P, Pasqualini F, Nebuloni M, Chen IH, Sozzani S, Austyn JM, Mantovani A, Sica A (2008) Divergent effects of hypoxia on dendritic cell functions. Blood 112(9):3723–3734. doi:10.1182/blood-2008-02-142091

    CAS  PubMed  Google Scholar 

  98. Wang Q, Liu C, Zhu F, Liu F, Zhang P, Guo C, Wang X, Li H, Ma C, Sun W, Zhang Y, Chen W, Zhang L (2010) Reoxygenation of hypoxia-differentiated dentritic cells induces Th1 and Th17 cell differentiation. Mol Immunol 47(4):922–931. doi:10.1016/j.molimm.2009.09.038

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Yang M, Ma C, Liu S, Sun J, Shao Q, Gao W, Zhang Y, Li Z, Xie Q, Dong Z, Qu X (2009) Hypoxia skews dendritic cells to a T helper type 2-stimulating phenotype and promotes tumour cell migration by dendritic cell-derived osteopontin. Immunology 128(1 Suppl):e237–249. doi:10.1111/j.1365-2567.2008.02954.x

    PubMed  Google Scholar 

  100. Priebe T, Platsoucas CD, Nelson JA (1990) Adenosine receptors and modulation of natural killer cell activity by purine nucleosides. Cancer Res 50(14):4328–4331

    CAS  PubMed  Google Scholar 

  101. Raskovalova T, Huang X, Sitkovsky M, Zacharia LC, Jackson EK, Gorelik E (2005) Gs protein-coupled adenosine receptor signaling and lytic function of activated NK cells. J Immunol 175(7):4383–4391

    CAS  PubMed  Google Scholar 

  102. 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. doi:10.1158/0008-5472.CAN-06-0478

    CAS  PubMed  Google Scholar 

  103. Fink T, Ebbesen P, Koppelhus U, Zachar V (2003) Natural killer cell-mediated basal and interferon-enhanced cytotoxicity against liver cancer cells is significantly impaired under in vivo oxygen conditions. Scand J Immunol 58(6):607–612

    CAS  PubMed  Google Scholar 

  104. Siemens DR, Hu N, Sheikhi AK, Chung E, Frederiksen LJ, Pross H, Graham CH (2008) Hypoxia increases tumor cell shedding of MHC class I chain-related molecule: role of nitric oxide. Cancer Res 68(12):4746–4753. doi:10.1158/0008-5472.CAN-08-0054

    CAS  PubMed  Google Scholar 

  105. Yamada N, Yamanegi K, Ohyama H, Hata M, Nakasho K, Futani H, Okamura H, Terada N (2012) Hypoxia downregulates the expression of cell surface MICA without increasing soluble MICA in osteosarcoma cells in a HIF-1alpha-dependent manner. Int J Oncol 41(6):2005–2012. doi:10.3892/ijo.2012.1630

    CAS  PubMed  Google Scholar 

  106. Sitkovsky MV, Lukashev D, Apasov S, Kojima H, Koshiba M, Caldwell C, Ohta A, Thiel M (2004) Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu Rev Immunol 22:657–682. doi:10.1146/annurev.immunol.22.012703.104731

    CAS  PubMed  Google Scholar 

  107. Eltzschig HK, Sitkovsky MV, Robson SC (2012) Purinergic signaling during inflammation. New Engl J Med 367(24):2322–2333. doi:10.1056/NEJMra1205750

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Chen JF, Eltzschig HK, Fredholm BB (2013) Adenosine receptors as drug targets–what are the challenges? Nature Rev Drug Discov 12(4):265–286. doi:10.1038/nrd3955

    CAS  Google Scholar 

  109. Ohta A, Sitkovsky M (2001) Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414(6866):916–920. doi:10.1038/414916a

    CAS  PubMed  Google Scholar 

  110. Sitkovsky MV, Ohta A (2005) The ‘danger’ sensors that STOP the immune response: the A2 adenosine receptors? Trends Immunol 26(6):299–304. doi:10.1016/j.it.2005.04.004

    CAS  PubMed  Google Scholar 

  111. Lukashev D, Ohta A, Apasov S, Chen JF, Sitkovsky M (2004) Cutting edge: physiologic attenuation of proinflammatory transcription by the Gs protein-coupled A2A adenosine receptor in vivo. J Immunol 173(1):21–24

    CAS  PubMed  Google Scholar 

  112. Mohsenin A, Mi T, Xia Y, Kellems RE, Chen JF, Blackburn MR (2007) Genetic removal of the A2A adenosine receptor enhances pulmonary inflammation, mucin production, and angiogenesis in adenosine deaminase-deficient mice. Am J Physiol Lung Cell Mol Physiol 293(3):L753–761. doi:10.1152/ajplung.00187.2007

    CAS  PubMed  Google Scholar 

  113. Nadeem A, Fan M, Ansari HR, Ledent C, Jamal Mustafa S (2007) Enhanced airway reactivity and inflammation in A2A adenosine receptor-deficient allergic mice. Am J Physiol Lung Cell Mol Physiol 292(6):L1335–1344. doi:10.1152/ajplung.00416.2006

    CAS  PubMed  Google Scholar 

  114. Alam MS, Kurtz CC, Wilson JM, Burnette BR, Wiznerowicz EB, Ross WG, Rieger JM, Figler RA, Linden J, Crowe SE, Ernst PB (2009) A2A adenosine receptor (AR) activation inhibits pro-inflammatory cytokine production by human CD4 + helper T cells and regulates Helicobacter-induced gastritis and bacterial persistence. Mucosal Immunol 2(3):232–242. doi:10.1038/mi.2009.4

    Google Scholar 

  115. Hasko G, Csoka B, Nemeth ZH, Vizi ES, Pacher P (2009) A(2B) adenosine receptors in immunity and inflammation. Trends Immunol 30(6):263–270. doi:10.1016/j.it.2009.04.001

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Koeppen M, Eckle T, Eltzschig HK (2011) Interplay of hypoxia and A2B adenosine receptors in tissue protection. Adv Pharmacol 61:145–186. doi:10.1016/B978-0-12-385526-8.00006-0

    CAS  PubMed  Google Scholar 

  117. Eckle T, Faigle M, Grenz A, Laucher S, Thompson LF, Eltzschig HK (2008) A2B adenosine receptor dampens hypoxia-induced vascular leak. Blood 111(4):2024–2035. doi:10.1182/blood-2007-10-117044

    CAS  PubMed  Google Scholar 

  118. Frick JS, MacManus CF, Scully M, Glover LE, Eltzschig HK, Colgan SP (2009) Contribution of adenosine A2B receptors to inflammatory parameters of experimental colitis. J Immunol 182(8):4957–4964. doi:10.4049/jimmunol.0801324

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Zhou Y, Mohsenin A, Morschl E, Young HW, Molina JG, Ma W, Sun CX, Martinez-Valdez H, Blackburn MR (2009) Enhanced airway inflammation and remodeling in adenosine deaminase-deficient mice lacking the A2B adenosine receptor. J Immunol 182(12):8037–8046. doi:10.4049/jimmunol.0900515

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Schingnitz U, Hartmann K, Macmanus CF, Eckle T, Zug S, Colgan SP, Eltzschig HK (2010) Signaling through the A2B adenosine receptor dampens endotoxin-induced acute lung injury. J Immunol 184(9):5271–5279. doi:10.4049/jimmunol.0903035

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Zhou Y, Schneider DJ, Morschl E, Song L, Pedroza M, Karmouty-Quintana H, Le T, Sun CX, Blackburn MR (2011) Distinct roles for the A2B adenosine receptor in acute and chronic stages of bleomycin-induced lung injury. J Immunol 186(2):1097–1106. doi:10.4049/jimmunol.1002907

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Restifo NP, Dudley ME, Rosenberg SA (2012) Adoptive immunotherapy for cancer: harnessing the T cell response. Nature reviews. Immunology 12(4):269–281. doi:10.1038/nri3191

    CAS  PubMed  Google Scholar 

  123. Vanneman M, Dranoff G (2012) Combining immunotherapy and targeted therapies in cancer treatment. Nature reviews. Cancer 12(4):237–251. doi:10.1038/nrc3237

    CAS  PubMed  Google Scholar 

  124. Drake CG, Doody AD, Mihalyo MA, Huang CT, Kelleher E, Ravi S, Hipkiss EL, Flies DB, Kennedy EP, Long M, McGary PW, Coryell L, Nelson WG, Pardoll DM, Adler AJ (2005) Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen. Cancer cell 7(3):239–249. doi:10.1016/j.ccr.2005.01.027

    CAS  PubMed Central  PubMed  Google Scholar 

  125. Bai A, Higham E, Eisen HN, Wittrup KD, Chen J (2008) Rapid tolerization of virus-activated tumor-specific CD8 + T cells in prostate tumors of TRAMP mice. Proc Natl Acad Sci U S A 105(35):13003–13008. doi:10.1073/pnas.0805599105

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Kerkar SP, Restifo NP (2012) Cellular constituents of immune escape within the tumor microenvironment. Cancer Res 72(13):3125–3130. doi:10.1158/0008–5472.CAN-11-4094

    CAS  PubMed  Google Scholar 

  127. Rabinovich GA, Gabrilovich D, Sotomayor EM (2007) Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 25:267–296. doi:10.1146/annurev.immunol.25.022106.141609

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Takagi H, King GL, Robinson GS, Ferrara N, Aiello LP (1996) Adenosine mediates hypoxic induction of vascular endothelial growth factor in retinal pericytes and endothelial cells. Invest Ophth Vis Sci 37(11):2165–2176

    CAS  Google Scholar 

  129. Coney AM, Marshall JM (1998) Role of adenosine and its receptors in the vasodilatation induced in the cerebral cortex of the rat by systemic hypoxia. J Physiol 509(Pt 2):507–518

    CAS  PubMed  Google Scholar 

  130. Kobayashi S, Conforti L, Pun RY, Millhorn DE (1998) Adenosine modulates hypoxia-induced responses in rat PC12 cells via the A2A receptor. J Physiol 508(Pt 1):95–107

    CAS  PubMed  Google Scholar 

  131. Fisher JW, Brookins J (2001) Adenosine A(2A) and A(2B) receptor activation of erythropoietin production. Am J Physiol Renal Physiol 281(5):F826–832

    CAS  PubMed  Google Scholar 

  132. Koos BJ, Maeda T (2001) Adenosine A(2A) receptors mediate cardiovascular responses to hypoxia in fetal sheep. Am J Physiol Heart Circ Physiol 280(1):H83–89

    CAS  PubMed  Google Scholar 

  133. Ohta A, Sitkovsky M (2011) Methylxanthines, inflammation, and cancer: fundamental mechanisms. Handb Exp Pharmacol (200):469–481. doi:10.1007/978-3-642-13443-2_19

    Google Scholar 

  134. 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 10(9):987–995

    CAS  PubMed Central  PubMed  Google Scholar 

  135. 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. doi:10.4049/jimmunol.1101845

    CAS  PubMed  Google Scholar 

  136. Zhang B (2010) CD73: a novel target for cancer immunotherapy. Cancer Res 70(16):6407–6411. doi:10.1158/0008-5472.CAN-10-1544

    CAS  PubMed Central  PubMed  Google Scholar 

  137. Beavis PA, Stagg J, Darcy PK, Smyth MJ (2012) CD73: a potent suppressor of antitumor immune responses. Trends Immunol 33(5):231–237. doi:10.1016/j.it.2012.02.009

    CAS  PubMed  Google Scholar 

  138. 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. doi:10.1073/pnas.0908801107

    CAS  PubMed Central  PubMed  Google Scholar 

  139. Stagg J, Divisekera U, Duret H, Sparwasser T, Teng MW, Darcy PK, Smyth MJ (2011) CD73-deficient mice have increased antitumor immunity and are resistant to experimental metastasis. Cancer Res 71(8):2892–2900. doi:10.1158/0008-5472.CAN-10-4246

    CAS  PubMed  Google Scholar 

  140. 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. doi:10.1158/0008-5472.CAN-12-0420

    CAS  PubMed  Google Scholar 

  141. Fredholm BB, Battig K, Holmen J, Nehlig A, Zvartau EE (1999) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 51(1):83–133

    CAS  PubMed  Google Scholar 

  142. Fredholm BB (2011) Notes on the history of caffeine use. Handb Exp Pharmacol (200):1–9. doi:10.1007/978-3-642-13443-2_1

    Google Scholar 

  143. Ohta A, Lukashev D, Jackson EK, Fredholm BB, Sitkovsky M (2007) 1,3,7-trimethylxanthine (caffeine) may exacerbate acute inflammatory liver injury by weakening the physiological immunosuppressive mechanism. J Immunol 179(11):7431–7438

    CAS  PubMed  Google Scholar 

  144. Lelo A, Miners JO, Robson R, Birkett DJ (1986) Assessment of caffeine exposure: caffeine content of beverages, caffeine intake, and plasma concentrations of methylxanthines. Clin Pharmacol Ther 39(1):54–59

    Google Scholar 

  145. Cook DG, Peacock JL, Feyerabend C, Carey IM, Jarvis MJ, Anderson HR, Bland JM (1996) Relation of caffeine intake and blood caffeine concentrations during pregnancy to fetal growth: prospective population based study. Bmj 313(7069):1358–1362

    CAS  PubMed  Google Scholar 

  146. Stensvold I, Jacobsen BK (1994) Coffee and cancer: a prospective study of 43,000 Norwegian men and women. Cancer Causes Control: CCC 5(5):401–408

    CAS  PubMed  Google Scholar 

  147. Veierod MB, Thelle DS, Laake P (1997) Diet and risk of cutaneous malignant melanoma: a prospective study of 50,757 Norwegian men and women. Int J Cancer (Journal international du cancer) 71(4):600–604

    CAS  Google Scholar 

  148. Shimazu T, Tsubono Y, Kuriyama S, Ohmori K, Koizumi Y, Nishino Y, Shibuya D, Tsuji I (2005) Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan. Int J Cancer (Journal international du cancer) 116(1):150–154. doi:10.1002/ijc.20989

    CAS  Google Scholar 

  149. Nkondjock A, Ghadirian P, Kotsopoulos J, Lubinski J, Lynch H, Kim-Sing C, Horsman D, Rosen B, Isaacs C, Weber B, Foulkes W, Ainsworth P, Tung N, Eisen A, Friedman E, Eng C, Sun P, Narod SA (2006) Coffee consumption and breast cancer risk among BRCA1 and BRCA2 mutation carriers. Int J Cancer (Journal international du cancer) 118(1):103–107. doi:10.1002/ijc.21296

    CAS  Google Scholar 

  150. Hirose K, Niwa Y, Wakai K, Matsuo K, Nakanishi T, Tajima K (2007) Coffee consumption and the risk of endometrial cancer: evidence from a case-control study of female hormone-related cancers in Japan. Cancer Sci 98(3):411–415. doi:10.1111/j.1349-7006.2007.00391.x

    CAS  PubMed  Google Scholar 

  151. Lee KJ, Inoue M, Otani T, Iwasaki M, Sasazuki S, Tsugane S, Group JS (2007) Coffee consumption and risk of colorectal cancer in a population-based prospective cohort of Japanese men and women. Int J Cancer (Journal international du cancer) 121(6):1312–1318. doi:10.1002/ijc.22778

    CAS  Google Scholar 

  152. Montella M, Polesel J, La Vecchia C, Dal Maso L, Crispo A, Crovatto M, Casarin P, Izzo F, Tommasi LG, Talamini R, Franceschi S (2007) Coffee and tea consumption and risk of hepatocellular carcinoma in Italy. Int J Cancer (Journal international du cancer) 120(7):1555–1559. doi:10.1002/ijc.22509

    CAS  Google Scholar 

  153. Ganmaa D, Willett WC, Li TY, Feskanich D, van Dam RM, Lopez-Garcia E, Hunter DJ, Holmes MD (2008) Coffee, tea, caffeine and risk of breast cancer: a 22-year follow-up. Int J Cancer (Journal international du cancer) 122(9):2071–2076. doi:10.1002/ijc.23336

    CAS  Google Scholar 

  154. Shimazu T, Inoue M, Sasazuki S, Iwasaki M, Kurahashi N, Yamaji T, Tsugane S, Study JSGMotJPHC-bP (2008) Coffee consumption and risk of endometrial cancer: a prospective study in Japan. Int J Cancer (Journal international du cancer) 123(10):2406–2410. doi:10.1002/ijc.23760

    CAS  Google Scholar 

  155. Waickman AT, Alme A, Senaldi L, Zarek PE, Horton M, Powell JD (2012) Enhancement of tumor immunotherapy by deletion of the A2A adenosine receptor. Cancer Immunol Immunother 61(6):917–926. doi:10.1007/s00262-011-1155-7

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. New England Inflammation and Tissue Protection Institute, Northeastern University, 113 Mugar Health Sciences Building, 360 Huntington Ave, 02115, Boston, MA, USA

    Akio Ohta & Michail Sitkovsky

Authors
  1. Akio Ohta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michail Sitkovsky
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michail Sitkovsky .

Editor information

Editors and Affiliations

  1. Translational Tumor Immunology, The Wistar Institute, Philadelphia, Pennsylvania, USA

    Dmitry I. Gabrilovich

  2. N Potomac, Maryland, USA

    Arthur Andrew Hurwitz

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Ohta, A., Sitkovsky, M. (2014). The Hypoxia-adenosinergic Immunosuppression and Redirection of Immune Response in Tumor Microenvironment. In: Gabrilovich, D., Hurwitz, A. (eds) Tumor-Induced Immune Suppression. Springer, New York, NY. https://doi.org/10.1007/978-1-4899-8056-4_14

Download citation

Publish with us

Policies and ethics

Search

Navigation