Skip to main content

Advertisement

Log in

Extracellular adenosine metabolism in immune cells in melanoma

  • Focussed Research Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Malignant melanoma is characterized by the development of chronic inflammation in the tumor microenvironment, which leads to a strong immunosuppression associated with a rapid tumor progression. Adenosine is considered as one of the main immunosuppressive factors in the tumor environment. It is produced via enzymatic hydrolysis of extracellular ATP by ectonucleotidases CD39 and CD73 localized on cell surface. Using the ret transgenic mouse melanoma model that closely mimics human melanoma, we demonstrated an increased frequency of ectonucleotidase-positive myeloid-derived suppressor cells (MDSCs) in melanoma lesions and lymphoid organs. Furthermore, we observed that conventional CD4+FoxP3 and CD8+ T cells infiltrating melanoma lesions of ret transgenic mice were distinctly enriched in the CD39+CD73+ subpopulation that co-expressed also PD-1. Ectonucleotidase expression was also up-regulated in CD4+ and CD8+ T cells upon activation. In addition, these ectoenzymes were largely found to be expressed on memory T cell compartment (in particular, on effector memory cells). Our data suggest that extracellular adenosine produced by regulatory T cells (Tregs) and MDSCs can suppress T cell effector functions through paracrine signaling. Another mechanism involves its production also by effector T cells and an inhibition of their anti-tumor reactivity via autocrine signaling as a part of the negative feedback loop. This mode of adenosine signaling could be also used by Tregs and MDSCs to enhance their immunosuppressive activity.

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

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Buzaid AC, Cochran AJ, Coit DG, Ding S, Eggermont AM, Flaherty KT, Gimotty PA, Kirkwood JM, McMasters KM, Mihm MC Jr, Morton DL, Ross MI, Sober AJ, Sondak VK (2009) Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27:6199–6206

    Article  PubMed  PubMed Central  Google Scholar 

  2. MacKie RM, Hauschild A, Eggermont AM (2009) Epidemiology of invasive cutaneous melanoma. Ann Oncol 20(Suppl 6):vi1–vi7

    Article  PubMed  PubMed Central  Google Scholar 

  3. Pflugfelder A, Kochs C, Blum A, Capellaro M, Czeschik C, Dettenborn T et al (2013) Malignant melanoma S3-guideline “diagnosis, therapy and follow-up of melanoma”. J Dtsch Dermatol Ges Suppl 6:1–116

    Google Scholar 

  4. Rosenberg SA (2011) Cell transfer immunotherapy for metastatic solid cancer–what clinicians need to know. Nat Rev Clin Oncol 8:577–585

    Article  PubMed  CAS  Google Scholar 

  5. Klebanoff CA, Acquavella N, Yu Z, Restifo NP (2011) Therapeutic cancer vaccines: are we there yet? Immunol Rev 239:27–44

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Gogas H, Polyzos A, Kirkwood J (2013) Immunotherapy for advanced melanoma: fulfilling the promise. Cancer Treat Rev 39:879–885

    Article  PubMed  CAS  Google Scholar 

  7. Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182:4499–4506

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Mantovani A (2010) Molecular pathways linking inflammation and cancer. Curr Mol Med 10:369–373

    Article  PubMed  CAS  Google Scholar 

  9. Gajewski TF, Fuertes M, Spaapen R, Zheng Y, Kline J (2011) Molecular profiling to identify relevant immune resistance mechanisms in the tumor microenvironment. Curr Opin Immunol 23:286–292

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Kanterman J, Sade-Feldman M, Baniyash M (2012) New insights into chronic inflammation-induced immunosuppression. Semin Cancer Biol 22:307–318

    Article  PubMed  CAS  Google Scholar 

  11. Coussens LM, Zitvogel L, Palucka AK (2013) Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 339:286–291

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Mougiakakos D, Choudhury A, Lladser A, Kiessling R, Johansson CC (2010) Regulatory T cells in cancer. Adv Cancer Res 107:57–117

    Article  PubMed  CAS  Google Scholar 

  13. Whiteside TL (2012) Disarming suppressor cells to improve immunotherapy. Cancer Immunol Immunother 61:283–288

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Filipazzi P, Huber V, Rivoltini L (2012) Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients. Cancer Immunol Immunother 61:255–263

    Article  PubMed  CAS  Google Scholar 

  16. Mantovani A, Sica A (2010) Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22:231–237

    Article  PubMed  CAS  Google Scholar 

  17. Lewis CE, De Palma M, Naldini L (2007) Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res 67:8429–8432

    Article  PubMed  CAS  Google Scholar 

  18. Fridlender ZG, Albelda SM (2012) Tumor-associated neutrophils: friend or foe? Carcinogenesis 33:949–955

    Article  PubMed  CAS  Google Scholar 

  19. Ma Y, Shurin GV, Gutkin DW, Shurin MR (2012) Tumor associated regulatory dendritic cells. Semin Cancer Biol 22:298–306

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Balkwill F (2009) Tumour necrosis factor and cancer. Nat Rev Cancer 9:361–371

    Article  PubMed  CAS  Google Scholar 

  21. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Singer K, Gottfried E, Kreutz M, Mackensen A (2011) Suppression of T-cell responses by tumor metabolites. Cancer Immunol Immunother 60:425–431

    Article  PubMed  CAS  Google Scholar 

  23. Ohta A, Gorelik E, Prasad SJ, Ronchese F, Lukashev D, Wong MKK, Huang X, Caldwell S, Liu K, Smith P, Chen J-F, Jackson EK, Apasov S, Abrams S, Sitkovsky M (2006) A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci USA 103:13132–13137

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Wang D, Dubois RN (2010) Eicosanoids and cancer. Nat Rev Cancer 10:181–193

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Carson DA, Iizasa T, Seto S, Carrera CJ, Kubota M, Willis EH, Wasson DB, Kajander O (1985) Metabolic basis for immune dysfunction in adenosine deaminase deficiency. Ann N Y Acad Sci 451:34–41

    Article  PubMed  CAS  Google Scholar 

  26. Hershfield MS (2005) New insights into adenosine-receptor-mediated immunosuppression and the role of adenosine in causing immunodeficiency associated with adenosine deaminase deficiency. Eur J Immunol 35:25–30

    Article  PubMed  CAS  Google Scholar 

  27. Apasov SG, Blackburn MR, Kellems RE, Smith PR, Sitkovsky MV (2001) Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling. J Clin Invest 108:131–141

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Ernst PB, Garrison JC, Thompson LF (2010) Much ado about adenosine: adenosine synthesis and function in regulatory T cell biology. J Immunol 185:1993–1998

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Whiteside TL, Mandapathil M, Schuler P (2011) The role of the adenosinergic pathway in immunosuppression mediated by human regulatory T cells (Treg). Curr Med Chem 18:5217–5223

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Whiteside TL (2014) Regulatory T cell subsets in human cancer: are they regulating for or against tumor progression? Cancer Immunol Immunother 63:67–72

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  32. Ghiringhelli F, Bruchard M, Chalmin F, Rébé C (2012) Production of adenosine by ectonucleotidases: a key factor in tumor immunoescape. J Biomed Biotechnol 2012:473712

    Article  PubMed  PubMed Central  Google Scholar 

  33. 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

    Article  PubMed  CAS  Google Scholar 

  34. Beavis PA, Stagg J, Darcy PK, Smyth MJ (2012) CD73: a potent suppressor of antitumor immune responses. Trends Immunol 33:231–237

    Article  PubMed  CAS  Google Scholar 

  35. 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 32:527–535

    PubMed  CAS  Google Scholar 

  36. Gottfried E, Kreutz M, Mackensen A (2012) Tumor metabolism as modulator of immune response and tumor progression. Semin Cancer Biol 22:335–341

    Article  PubMed  CAS  Google Scholar 

  37. 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 14:5947–5952

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  39. Stagg J, Smyth MJ (2010) Extracellular adenosine triphosphate and adenosine in cancer. Oncogene 29:5346–5358

    Article  PubMed  CAS  Google Scholar 

  40. Allard B, Turcotte M, Stagg J (2012) CD73-generated adenosine: orchestrating the tumor-stroma interplay to promote cancer growth. J Biomed Biotechnol 2012:485156

    Article  PubMed  PubMed Central  Google Scholar 

  41. Fredholm BB, Chern Y, Franco R, Sitkovsky M (2007) Aspects of the general biology of adenosine A2A signaling. Prog Neurobiol 83:263–276

    Article  PubMed  CAS  Google Scholar 

  42. Majumdar S, Aggarwal BB (2003) Adenosine suppresses activation of nuclear factor-kappaB selectively induced by tumor necrosis factor in different cell types. Oncogene 22:1206–1218

    Article  PubMed  CAS  Google Scholar 

  43. 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 99:386–395

    Article  PubMed  CAS  Google Scholar 

  44. 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 90:1600–1610

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  46. 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 67:5949–5956

    Article  PubMed  CAS  Google Scholar 

  47. 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 272:25881–25889

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  49. MacKenzie WM, Hoskin DW, Blay J (2002) Adenosine suppresses alpha(4)beta(7) integrin-mediated adhesion of T lymphocytes to colon adenocarcinoma cells. Exp Cell Res 276:90–100

    Article  PubMed  CAS  Google Scholar 

  50. 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 204:1257–1265

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  51. 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 112:1822–1831

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  52. Csóka B, Selmeczy Z, Koscsó B, Németh ZH, Pacher P, Murray PJ, Kepka-Lenhart D, Morris SM Jr, Gause WC, Leibovich SJ, Haskó G (2012) Adenosine promotes alternative macrophage activation via A2A and A2B receptors. FASEB J 26:376–386

    Article  PubMed  PubMed Central  Google Scholar 

  53. 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 66:7758–7765

    Article  PubMed  CAS  Google Scholar 

  54. Junger WG (2011) Immune cell regulation by autocrine purinergic signalling. Nat Rev Immunol 11:201–212

    Article  PubMed  CAS  Google Scholar 

  55. 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 121:2371–2382

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  56. Knapp K, Zebisch M, Pippel J, El-Tayeb A, Muller CE, Strater N (2012) Crystal structure of the human ecto-5′-nucleotidase (CD73): insights into the regulation of purinergic signaling. Structure 20:2161–2173

    Article  PubMed  CAS  Google Scholar 

  57. Strater N (2006) Ecto-5′-nucleotidase: structure function relationships. Purinergic Signal 2:343–350

    Article  PubMed  PubMed Central  Google Scholar 

  58. 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 71:2892–2900

    Article  PubMed  CAS  Google Scholar 

  59. 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 107:1547–1552

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  60. 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 70:2245–2255

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  61. Stagg J, Beavis PA, Divisekera U, Liu MC, Moller A, Darcy PK, Smyth MJ (2012) CD73-deficient mice are resistant to carcinogenesis. Cancer Res 72:2190–2196

    Article  PubMed  CAS  Google Scholar 

  62. Pere H, Tanchot C, Bayry J, Terme M, Taieb J, Badoual C, Adotevi O, Merillon N, Marcheteau E, Quillien VR, Banissi C, Carpentier A, Sandoval F, Nizard M, Quintin-Colonna F, Kroemer G, Fridman WH, Zitvogel L, Oudard SP, Tartour E (2012) Comprehensive analysis of current approaches to inhibit regulatory T cells in cancer. Oncoimmunology 1:326–333

    Article  PubMed  PubMed Central  Google Scholar 

  63. Mandapathil M, Hilldorfer B, Szczepanski MJ, Czystowska M, Szajnik M, Ren J, Lang S, Jackson EK, Gorelik E, Whiteside TL (2010) Generation and accumulation of immunosuppressive adenosine by human CD4 + CD25highFOXP3 + regulatory T cells. J Biol Chem 285:7176–7186

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  64. Mandapathil M, Whiteside TL (2011) Targeting human inducible regulatory T cells (Tr1) in patients with cancer: blocking of adenosine-prostaglandin E2 cooperation. Expert Opin Biol Ther 11:1203–1214

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  65. Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25 + CD4 + regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352

    Article  PubMed  CAS  Google Scholar 

  66. Shevach EM (2009) Mechanisms of foxp3 + T regulatory cell-mediated suppression. Immunity 30:636–645

    Article  PubMed  CAS  Google Scholar 

  67. Romio M, Reinbeck B, Bongardt S, Huls S, Burghoff S, Schrader J (2011) Extracellular purine metabolism and signaling of CD73-derived adenosine in murine Treg and Teff cells. Am J Physiol Cell Physiol 301:C530–C539

    Article  PubMed  CAS  Google Scholar 

  68. Ostrand-Rosenberg S (2010) Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother 59:1593–1600

    Article  PubMed  PubMed Central  Google Scholar 

  69. Peranzoni E, Zilio S, Marigo I, Dolcetti L, Zanovello P, Mandruzzato S, Bronte V (2010) Myeloid-derived suppressor cell heterogeneity and subset definition. Curr Opin Immunol 22:238–244

    Article  PubMed  CAS  Google Scholar 

  70. Youn JI, Nagaraj S, Collazo M, Gabrilovich DI (2008) Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol 181:5791–5802

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  71. Condamine T, Gabrilovich DI (2011) Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol 32:19–25

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  72. Lu T, Gabrilovich DI (2012) Molecular pathways: tumor-infiltrating myeloid cells and reactive oxygen species in regulation of tumor microenvironment. Clin Cancer Res 18:4877–4882

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  73. 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 187:6120–6129

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  74. Kato M, Takahashi M, Akhand AA, Liu W, Dai Y, Shimizu S, Iwamoto T, Suzuki H, Nakashima I (1998) Transgenic mouse model for skin malignant melanoma. Oncogene 17:1885–1888

    Article  PubMed  CAS  Google Scholar 

  75. Umansky V, Abschuetz O, Osen W, Ramacher M, Zhao F, Kato M, Schadendorf D (2008) Melanoma-specific memory T cells are functionally active in Ret transgenic mice without macroscopic tumors. Cancer Res 68:9451–9458

    Article  PubMed  CAS  Google Scholar 

  76. Shevchenko I, Bazhin AV, Umansky V (2012) Comment on “Adenosinergic regulation of the expansion and immunosuppressive activity of CD11b(+)Gr1(+) cells”. J Immunol 188:2929–2930

    Article  PubMed  CAS  Google Scholar 

  77. Hyman MC, Petrovic-Djergovic D, Visovatti SH, Liao H, Yanamadala S, Bouis D, Su EJ, Lawrence DA, Broekman MJ, Marcus AJ, Pinsky DJ (2009) Self-regulation of inflammatory cell trafficking in mice by the leukocyte surface apyrase CD39. J Clin Invest 119:1136–1149

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  78. Chen Y, Yao Y, Sumi Y, Li A, To UK, Elkhal A, Inoue Y, Woehrle T, Zhang Q, Hauser C, Junger WG (2010) Purinergic signaling: a fundamental mechanism in neutrophil activation. Sci Signal 3:ra45

    PubMed  Google Scholar 

  79. Meyer C, Sevko A, Ramacher M, Bazhin AV, Falk CS, Osen W, Borrello I, Kato M, Schadendorf D, Baniyash M, Umansky V (2011) Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model. Proc Natl Acad Sci U S A 108:17111–17116

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  80. Regateiro FS, Howie D, Nolan KF, Agorogiannis EI, Greaves DR, Cobbold SP, Waldmann H (2011) Generation of anti-inflammatory adenosine by leukocytes is regulated by TGF-beta. Eur J Immunol 41:2955–2965

    Article  PubMed  CAS  Google Scholar 

  81. Chalmin F, Mignot G, Bruchard M, Chevriaux A, Vegran F, Hichami A, Ladoire S, Derangere V, Vincent J, Masson D, Robson SC, Eberl G, Pallandre JR, Borg C, Ryffel B, Apetoh L, Rebe C, Ghiringhelli F (2012) Stat3 and Gfi-1 transcription factors control Th17 cell immunosuppressive activity via the regulation of ectonucleotidase expression. Immunity 36:362–373

    Article  PubMed  CAS  Google Scholar 

  82. Umansky V, Sevko A (2012) Overcoming immunosuppression in the melanoma microenvironment induced by chronic inflammation. Cancer Immunol Immunother 61:275–282

    Article  PubMed  CAS  Google Scholar 

  83. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264

    Article  PubMed  CAS  Google Scholar 

  84. Josefowicz SZ, Lu LF, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564

    Article  PubMed  CAS  Google Scholar 

  85. Yip L, Woehrle T, Corriden R, Hirsh M, Chen Y, Inoue Y, Ferrari V, Insel PA, Junger WG (2009) Autocrine regulation of T-cell activation by ATP release and P2X7 receptors. FASEB J 23:1685–1693

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  86. Schenk U, Frascoli M, Proietti M, Geffers R, Traggiai E, Buer J, Ricordi C, Westendorf AM, Grassi F (2011) ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors. Sci Signal 4:ra12

    PubMed  Google Scholar 

  87. Horenstein AL, Chillemi A, Zaccarello G, Bruzzone S, Quarona V, Zito A, Serra S, Malavasi F (2013) A CD38/CD203a/CD73 ectoenzymatic pathway independent of CD39 drives a novel adenosinergic loop in human T lymphocytes. Oncoimmunology 2:e26246

    Article  PubMed  PubMed Central  Google Scholar 

  88. Sallusto F, Geginat J, Lanzavecchia A (2004) Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol 22:745–763

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This project has been funded by a grant from the Cooperation Program in Cancer Research between German Cancer Research Center (DKFZ) and Ministry of Science and Technology of Israel (MOST) (CA157, to Viktor Umansky) and by a grant from Else-Kröner Fresenius Foundation (2010.A124, to Viktor Umansky and Alexandr V. Bazhin).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Viktor Umansky.

Additional information

This paper is a Focussed Research Review based on a presentation given at the Thirteenth International Conference on Progress in Vaccination against Cancer (PIVAC 13), held in Amsterdam, the Netherlands, October 2nd–4th, 2013. It is part of a CII series of Focussed Research Reviews and meeting report.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Umansky, V., Shevchenko, I., Bazhin, A.V. et al. Extracellular adenosine metabolism in immune cells in melanoma. Cancer Immunol Immunother 63, 1073–1080 (2014). https://doi.org/10.1007/s00262-014-1553-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-014-1553-8

Keywords

Navigation