Seminars in Immunopathology

, Volume 40, Issue 5, pp 465–475 | Cite as

Extracellular vesicles in cancer immune responses: roles of purinergic receptors

  • Michael W GranerEmail author


Extracellular vesicles (EVs) are nano- to micro-scale membrane-enclosed vesicles that are released from presumably all cell types. Tumor cells and immune cells are prodigious generators of EVs often with competing phenotypes in terms of immune suppression versus immune stimulation. Purinergic receptors, proteins that bind diverse purine nucleotides and nucleosides (ATP, ADP, AMP, adenosine), are widely expressed across tissues and cell types, and are prominent players in immune and tumor cell nucleotide metabolism. The effects of purinergic receptor stimulation or agonism tend to produce inflammatory responses that may aid immune stimulation but may also provoke various immune suppression mechanisms, particularly in the tumor microenvironment. EVs released by cells following receptor stimulation are frequently pro-inflammatory, but often also pro-thrombolytic; these EVs may generate an environment that favors tumor progression at the cost of an effective immune response. Purinergic signaling pathways are becoming more recognized as valuable targets in various therapeutic scenarios, including cancer. It is possible that some of those clinically relevant compounds might also impact EV secretion and/or phenotype, which would hopefully capitalize on the immune stimulatory properties of purinergic signaling while minimizing the immune suppressive consequences. This review covers a relatively understudied area in EV biology, but even so, focuses almost exclusively on the purinergic receptors in a very limited capacity. There is much more to evaluate and incorporate into our understanding of extracellular nucleotides in EV biology, and we hope this work prompts further discovery.


  1. 1.
    Yanez-Mo M, Siljander PR, Andreu Z, Zavec AB, Borras FE, Buzas EI, Buzas K, Casal E, Cappello F, Carvalho J, Colas E, Cordeiro-da Silva A, Fais S, Falcon-Perez JM, Ghobrial IM, Giebel B, Gimona M, Graner M, Gursel I, Gursel M, Heegaard NH, Hendrix A, Kierulf P, Kokubun K, Kosanovic M, Kralj-Iglic V, Kramer-Albers EM, Laitinen S, Lasser C, Lener T, Ligeti E, Line A, Lipps G, Llorente A, Lotvall J, Mancek-Keber M, Marcilla A, Mittelbrunn M, Nazarenko I, Nolte-'t Hoen EN, Nyman TA, O'Driscoll L, Olivan M, Oliveira C, Pallinger E, Del Portillo HA, Reventos J, Rigau M, Rohde E, Sammar M, Sanchez-Madrid F, Santarem N, Schallmoser K, Ostenfeld MS, Stoorvogel W, Stukelj R, Van der Grein SG, Vasconcelos MH, Wauben MH, De Wever O (2015) Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles 4:27066. CrossRefPubMedGoogle Scholar
  2. 2.
    De Toro J, Herschlik L, Waldner C, Mongini C (2015) Emerging roles of exosomes in normal and pathological conditions: new insights for diagnosis and therapeutic applications. Front Immunol 6:203. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Benito-Martin A, Di Giannatale A, Ceder S, Peinado H (2015) The new deal: a potential role for secreted vesicles in innate immunity and tumor progression. Front Immunol 6:66. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Greening DW, Gopal SK, Xu R, Simpson RJ, Chen W (2015) Exosomes and their roles in immune regulation and cancer. Semin Cell Dev Biol 40:72–81. CrossRefPubMedGoogle Scholar
  5. 5.
    Hellwinkel JE, Madsen H, Graner MW (2015) Immune modulation by tumor-derived extracellular vesicles in glioblastoma. Molecular considerations and evolving surgical management issues in the treatment of patients with a brain tumor. In: InTech, Rijeka. Google Scholar
  6. 6.
    Camisaschi C, Vallacchi V, Vergani E, Tazzari M, Ferro S, Tuccitto A, Kuchuk O, Shahaj E, Sulsenti R, Castelli C, Rodolfo M, Rivoltini L, Huber V (2016) Targeting immune regulatory networks to counteract immune suppression in cancer. Vaccines (Basel) 4(4). CrossRefPubMedCentralGoogle Scholar
  7. 7.
    Kunigelis KE, Graner MW (2015) The dichotomy of tumor exosomes (TEX) in cancer immunity: is it all in the ConTEXt? Vaccines (Basel) 3(4):1019–1051. CrossRefGoogle Scholar
  8. 8.
    Wen C, Seeger RC, Fabbri M, Wang L, Wayne AS, Jong AY (2017) Biological roles and potential applications of immune cell-derived extracellular vesicles. J Extracell Vesicles 6(1):1400370. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    De Robertis ED, Bennett HS (1955) Some features of the submicroscopic morphology of synapses in frog and earthworm. J Biophys Biochem Cytol 1(1):47–58CrossRefPubMedCentralGoogle Scholar
  10. 10.
    Monleon I, Martinez-Lorenzo MJ, Monteagudo L, Lasierra P, Taules M, Iturralde M, Pineiro A, Larrad L, Alava MA, Naval J, Anel A (2001) Differential secretion of Fas ligand- or APO2 ligand/TNF-related apoptosis-inducing ligand-carrying microvesicles during activation-induced death of human T cells. J Immunol 167(12):6736–6744CrossRefPubMedGoogle Scholar
  11. 11.
    Zuccato E, Blott EJ, Holt O, Sigismund S, Shaw M, Bossi G, Griffiths GM (2007) Sorting of Fas ligand to secretory lysosomes is regulated by mono-ubiquitylation and phosphorylation. J Cell Sci 120(Pt 1):191–199. CrossRefPubMedGoogle Scholar
  12. 12.
    Brody I, Ronquist G, Gottfries A (1983) Ultrastructural localization of the prostasome—an organelle in human seminal plasma. Ups J Med Sci 88(2):63–80CrossRefPubMedGoogle Scholar
  13. 13.
    Bilen MA, Pan T, Lee YC, Lin SC, Yu G, Pan J, Hawke D, Pan BF, Vykoukal J, Gray K, Satcher RL, Gallick GE, Yu-Lee LY, Lin SH (2017) Proteomics profiling of exosomes from primary mouse osteoblasts under proliferation versus mineralization conditions and characterization of their uptake into prostate cancer cells. J Proteome Res 16(8):2709–2728. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Greco V, Hannus M, Eaton S (2001) Argosomes: a potential vehicle for the spread of morphogens through epithelia. Cell 106(5):633–645CrossRefPubMedGoogle Scholar
  15. 15.
    Lee TH, D'Asti E, Magnus N, Al-Nedawi K, Meehan B, Rak J (2011) Microvesicles as mediators of intercellular communication in cancer—the emerging science of cellular ‘debris’. Semin Immunopathol 33(5):455–467. CrossRefPubMedGoogle Scholar
  16. 16.
    Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C (1987) Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem 262(19):9412–9420PubMedGoogle Scholar
  17. 17.
    Piper RC, Luzio JP (2001) Late endosomes: sorting and partitioning in multivesicular bodies. Traffic 2(9):612–621CrossRefPubMedGoogle Scholar
  18. 18.
    Gould SJ, Raposo G (2013) As we wait: coping with an imperfect nomenclature for extracellular vesicles. J Extracell Vesicles 2. CrossRefGoogle Scholar
  19. 19.
    Zhang H, Freitas D, Kim HS, Fabijanic K, Li Z, Chen H, Mark MT, Molina H, Martin AB, Bojmar L, Fang J, Rampersaud S, Hoshino A, Matei I, Kenific CM, Nakajima M, Mutvei AP, Sansone P, Buehring W, Wang H, Jimenez JP, Cohen-Gould L, Paknejad N, Brendel M, Manova-Todorova K, Magalhaes A, Ferreira JA, Osorio H, Silva AM, Massey A, Cubillos-Ruiz JR, Galletti G, Giannakakou P, Cuervo AM, Blenis J, Schwartz R, Brady MS, Peinado H, Bromberg J, Matsui H, Reis CA, Lyden D (2018) Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation. Nat Cell Biol 20(3):332–343. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Gyorgy B, Szabo TG, Pasztoi M, Pal Z, Misjak P, Aradi B, Laszlo V, Pallinger E, Pap E, Kittel A, Nagy G, Falus A, Buzas EI (2011) Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci 68(16):2667–2688. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Xu R, Greening DW, Rai A, Ji H, Simpson RJ (2015) Highly-purified exosomes and shed microvesicles isolated from the human colon cancer cell line LIM1863 by sequential centrifugal ultrafiltration are biochemically and functionally distinct. Methods 87:11–25. CrossRefPubMedGoogle Scholar
  22. 22.
    Jeppesen DK, Hvam ML, Primdahl-Bengtson B, Boysen AT, Whitehead B, Dyrskjot L, Orntoft TF, Howard KA, Ostenfeld MS (2014) Comparative analysis of discrete exosome fractions obtained by differential centrifugation. J Extracell Vesicles 3:25011. CrossRefPubMedGoogle Scholar
  23. 23.
    Willms E, Johansson HJ, Mager I, Lee Y, Blomberg KE, Sadik M, Alaarg A, Smith CI, Lehtio J, El Andaloussi S, Wood MJ, Vader P (2016) Cells release subpopulations of exosomes with distinct molecular and biological properties. Sci Rep 6:22519. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kowal J, Arras G, Colombo M, Jouve M, Morath JP, Primdal-Bengtson B, Dingli F, Loew D, Tkach M, Thery C (2016) Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci U S A 113(8):E968–E977. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Graner MW, Alzate O, Dechkovskaia AM, Keene JD, Sampson JH, Mitchell DA, Bigner DD (2009) Proteomic and immunologic analyses of brain tumor exosomes. FASEB J 23(5):1541–1557. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Griffiths SG, Cormier MT, Clayton A, Doucette AA (2017) Differential proteome analysis of extracellular vesicles from breast cancer cell lines by chaperone affinity enrichment. Proteomes 5(4). CrossRefPubMedCentralGoogle Scholar
  27. 27.
    Wolfers J, Lozier A, Raposo G, Regnault A, Thery C, Masurier C, Flament C, Pouzieux S, Faure F, Tursz T, Angevin E, Amigorena S, Zitvogel L (2001) Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med 7(3):297–303CrossRefPubMedGoogle Scholar
  28. 28.
    Altieri SL, Khan AN, Tomasi TB (2004) Exosomes from plasmacytoma cells as a tumor vaccine. J Immunother 27(4):282–288CrossRefPubMedGoogle Scholar
  29. 29.
    Whiteside TL (2017a) Exosomes in cancer: another mechanism of tumor-induced immune suppression. Adv Exp Med Biol 1036:81–89. CrossRefPubMedGoogle Scholar
  30. 30.
    Czernek L, Duchler M (2017) Functions of cancer-derived extracellular vesicles in immunosuppression. Arch Immunol Ther Exp 65(4):311–323. CrossRefGoogle Scholar
  31. 31.
    Dai S, Wei D, Wu Z, Zhou X, Wei X, Huang H, Li G (2008) Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol Ther 16(4):782–790. CrossRefPubMedGoogle Scholar
  32. 32.
    Andrews DW, Resnicoff M, Flanders AE, Kenyon L, Curtis M, Merli G, Baserga R, Iliakis G, Aiken RD (2001) Results of a pilot study involving the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor in malignant astrocytomas. J Clin Oncol 19(8):2189–2200. CrossRefPubMedGoogle Scholar
  33. 33.
    Harshyne LA, Hooper KM, Andrews EG, Nasca BJ, Kenyon LC, Andrews DW, Hooper DC (2015) Glioblastoma exosomes and IGF-1R/AS-ODN are immunogenic stimuli in a translational research immunotherapy paradigm. Cancer Immunol Immunother 64(3):299–309. CrossRefPubMedGoogle Scholar
  34. 34.
    Besse B, Charrier M, Lapierre V, Dansin E, Lantz O, Planchard D, Le Chevalier T, Livartoski A, Barlesi F, Laplanche A, Ploix S, Vimond N, Peguillet I, Thery C, Lacroix L, Zoernig I, Dhodapkar K, Dhodapkar M, Viaud S, Soria JC, Reiners KS, Pogge von Strandmann E, Vely F, Rusakiewicz S, Eggermont A, Pitt JM, Zitvogel L, Chaput N (2016) Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC. Oncoimmunology 5(4):e1071008. CrossRefPubMedGoogle Scholar
  35. 35.
    Escudier B, Dorval T, Chaput N, Andre F, Caby MP, Novault S, Flament C, Leboulaire C, Borg C, Amigorena S, Boccaccio C, Bonnerot C, Dhellin O, Movassagh M, Piperno S, Robert C, Serra V, Valente N, Le Pecq JB, Spatz A, Lantz O, Tursz T, Angevin E, Zitvogel L (2005) Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial. J Transl Med 3(1):10CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Whiteside TL (2016) Exosomes and tumor-mediated immune suppression. J Clin Invest 126(4):1216–1223. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Whiteside TL (2017b) Exosomes carrying immunoinhibitory proteins and their role in cancer. Clin Exp Immunol 189(3):259–267. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Chen W, Jiang J, Xia W, Huang J (2017) Tumor-related exosomes contribute to tumor-promoting microenvironment: an immunological perspective. J Immunol Res 2017:1073947. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Qu X, Tang Y, Hua S (2018) Immunological approaches towards cancer and inflammation: a cross talk. Front Immunol 9:563. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Idzko M, Ferrari D, Eltzschig HK (2014) Nucleotide signalling during inflammation. Nature 509(7500):310–317. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Roger S, Jelassi B, Couillin I, Pelegrin P, Besson P, Jiang LH (2015) Understanding the roles of the P2X7 receptor in solid tumour progression and therapeutic perspectives. Biochim Biophys Acta 1848(10 Pt B):2584–2602. CrossRefPubMedGoogle Scholar
  42. 42.
    Burnstock G (2017) Purinergic signalling: therapeutic developments. Front Pharmacol 8:661. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Di Virgilio F, Adinolfi E (2017) Extracellular purines, purinergic receptors and tumor growth. Oncogene 36(3):293–303. CrossRefPubMedGoogle Scholar
  44. 44.
    Williams M, Jarvis MF (2000) Purinergic and pyrimidinergic receptors as potential drug targets. Biochem Pharmacol 59(10):1173–1185CrossRefPubMedGoogle Scholar
  45. 45.
    Yegutkin GG (2014) Enzymes involved in metabolism of extracellular nucleotides and nucleosides: functional implications and measurement of activities. Crit Rev Biochem Mol Biol 49(6):473–497. CrossRefPubMedGoogle Scholar
  46. 46.
    Falzoni S, Donvito G, Di Virgilio F (2013) Detecting adenosine triphosphate in the pericellular space. Interface Focus 3(3):20120101. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Lazarowski ER (2012) Vesicular and conductive mechanisms of nucleotide release. Purinergic Signal 8(3):359–373. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Burnstock G (2018) The therapeutic potential of purinergic signalling. Biochem Pharmacol 151:157–165. CrossRefPubMedGoogle Scholar
  49. 49.
    Burnstock G (2014) Purinergic signalling: from discovery to current developments. Exp Physiol 99(1):16–34. CrossRefPubMedGoogle Scholar
  50. 50.
    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. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    North RA (2016) P2X receptors. Philos Trans R Soc Lond Ser B Biol Sci 371(1700):20150427. CrossRefGoogle Scholar
  52. 52.
    Hasko G, Antonioli L, Cronstein BN (2018) Adenosine metabolism, immunity and joint health. Biochem Pharmacol 151:307–313. CrossRefPubMedGoogle Scholar
  53. 53.
    Satoh T, Otsuka A, Contassot E, French LE (2015) The inflammasome and IL-1beta: implications for the treatment of inflammatory diseases. Immunotherapy 7(3):243–254. CrossRefPubMedGoogle Scholar
  54. 54.
    Lopez-Castejon G, Brough D (2011) Understanding the mechanism of IL-1beta secretion. Cytokine Growth Factor Rev 22(4):189–195. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Dubyak GR (2012) P2X7 receptor regulation of non-classical secretion from immune effector cells. Cell Microbiol 14(11):1697–1706. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    MacKenzie A, Wilson HL, Kiss-Toth E, Dower SK, North RA, Surprenant A (2001) Rapid secretion of interleukin-1beta by microvesicle shedding. Immunity 15(5):825–835CrossRefPubMedGoogle Scholar
  57. 57.
    Li Q, Barres BA (2018) Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol 18(4):225–242. CrossRefPubMedGoogle Scholar
  58. 58.
    Bianco F, Pravettoni E, Colombo A, Schenk U, Moller T, Matteoli M, Verderio C (2005) Astrocyte-derived ATP induces vesicle shedding and IL-1 beta release from microglia. J Immunol 174(11):7268–7277CrossRefPubMedGoogle Scholar
  59. 59.
    Bianco F, Perrotta C, Novellino L, Francolini M, Riganti L, Menna E, Saglietti L, Schuchman EH, Furlan R, Clementi E, Matteoli M, Verderio C (2009) Acid sphingomyelinase activity triggers microparticle release from glial cells. EMBO J 28(8):1043–1054. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Bowser DN, Khakh BS (2007) Vesicular ATP is the predominant cause of intercellular calcium waves in astrocytes. J Gen Physiol 129(6):485–491. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Moro S, Guo D, Camaioni E, Boyer JL, Harden TK, Jacobson KA (1998) Human P2Y1 receptor: molecular modeling and site-directed mutagenesis as tools to identify agonist and antagonist recognition sites. J Med Chem 41(9):1456–1466. CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Sakaki H, Tsukimoto M, Harada H, Moriyama Y, Kojima S (2013) Autocrine regulation of macrophage activation via exocytosis of ATP and activation of P2Y11 receptor. PLoS One 8(4):e59778. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Murray PJ (2017) Macrophage polarization. Annu Rev Physiol 79:541–566. CrossRefPubMedGoogle Scholar
  64. 64.
    Pizzirani C, Ferrari D, Chiozzi P, Adinolfi E, Sandona D, Savaglio E, Di Virgilio F (2007) Stimulation of P2 receptors causes release of IL-1beta-loaded microvesicles from human dendritic cells. Blood 109(9):3856–3864. CrossRefPubMedGoogle Scholar
  65. 65.
    Baroni M, Pizzirani C, Pinotti M, Ferrari D, Adinolfi E, Calzavarini S, Caruso P, Bernardi F, Di Virgilio F (2007) Stimulation of P2 (P2X7) receptors in human dendritic cells induces the release of tissue factor-bearing microparticles. FASEB J 21(8):1926–1933. CrossRefPubMedGoogle Scholar
  66. 66.
    Qu Y, Franchi L, Nunez G, Dubyak GR (2007) Nonclassical IL-1 beta secretion stimulated by P2X7 receptors is dependent on inflammasome activation and correlated with exosome release in murine macrophages. J Immunol 179(3):1913–1925CrossRefPubMedGoogle Scholar
  67. 67.
    Qu Y, Ramachandra L, Mohr S, Franchi L, Harding CV, Nunez G, Dubyak GR (2009) P2X7 receptor-stimulated secretion of MHC class II-containing exosomes requires the ASC/NLRP3 inflammasome but is independent of caspase-1. J Immunol 182(8):5052–5062. CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Rothmeier AS, Marchese P, Petrich BG, Furlan-Freguia C, Ginsberg MH, Ruggeri ZM, Ruf W (2015) Caspase-1-mediated pathway promotes generation of thromboinflammatory microparticles. J Clin Invest 125(4):1471–1484. CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Novick D, Kim S, Kaplanski G, Dinarello CA (2013) Interleukin-18, more than a Th1 cytokine. Semin Immunol 25(6):439–448. CrossRefPubMedGoogle Scholar
  70. 70.
    Gulinelli S, Salaro E, Vuerich M, Bozzato D, Pizzirani C, Bolognesi G, Idzko M, Di Virgilio F, Ferrari D (2012) IL-18 associates to microvesicles shed from human macrophages by a LPS/TLR-4 independent mechanism in response to P2X receptor stimulation. Eur J Immunol 42(12):3334–3345. CrossRefPubMedGoogle Scholar
  71. 71.
    Thomas LM, Salter RD (2010) Activation of macrophages by P2X7-induced microvesicles from myeloid cells is mediated by phospholipids and is partially dependent on TLR4. J Immunol 185(6):3740–3749. CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Barbera-Cremades M, Gomez AI, Baroja-Mazo A, Martinez-Alarcon L, Martinez CM, de Torre-Minguela C, Pelegrin P (2017) P2X7 receptor induces tumor necrosis factor-alpha converting enzyme activation and release to boost TNF-alpha production. Front Immunol 8:862. CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Aymeric L, Apetoh L, Ghiringhelli F, Tesniere A, Martins I, Kroemer G, Smyth MJ, Zitvogel L (2010) Tumor cell death and ATP release prime dendritic cells and efficient anticancer immunity. Cancer Res 70(3):855–858. CrossRefPubMedGoogle Scholar
  74. 74.
    Di Virgilio F, Vuerich M (2015) Purinergic signaling in the immune system. Auton Neurosci 191:117–123. CrossRefPubMedGoogle Scholar
  75. 75.
    la Sala A, Sebastiani S, Ferrari D, Di Virgilio F, Idzko M, Norgauer J, Girolomoni G (2002) Dendritic cells exposed to extracellular adenosine triphosphate acquire the migratory properties of mature cells and show a reduced capacity to attract type 1 T lymphocytes. Blood 99(5):1715–1722CrossRefPubMedGoogle Scholar
  76. 76.
    Frascoli M, Marcandalli J, Schenk U, Grassi F (2012) Purinergic P2X7 receptor drives T cell lineage choice and shapes peripheral gammadelta cells. J Immunol 189(1):174–180. CrossRefPubMedGoogle Scholar
  77. 77.
    Zhao Y, Niu C, Cui J (2018) Gamma-delta (gammadelta) T cells: friend or foe in cancer development? J Transl Med 16(1):3. CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Shinohara Y, Tsukimoto M (2017) Adenine nucleotides attenuate murine T cell activation induced by Concanavalin A or T cell receptor stimulation. Front Pharmacol 8:986. CrossRefPubMedGoogle Scholar
  79. 79.
    Trabanelli S, Ocadlikova D, Gulinelli S, Curti A, Salvestrini V, Vieira RP, Idzko M, Di Virgilio F, Ferrari D, Lemoli RM (2012) Extracellular ATP exerts opposite effects on activated and regulatory CD4+ T cells via purinergic P2 receptor activation. J Immunol 189(3):1303–1310. CrossRefPubMedGoogle Scholar
  80. 80.
    Veglia F, Perego M, Gabrilovich D (2018) Myeloid-derived suppressor cells coming of age. Nat Immunol 19(2):108–119. CrossRefPubMedGoogle Scholar
  81. 81.
    Bianchi G, Vuerich M, Pellegatti P, Marimpietri D, Emionite L, Marigo I, Bronte V, Di Virgilio F, Pistoia V, Raffaghello L (2014) ATP/P2X7 axis modulates myeloid-derived suppressor cell functions in neuroblastoma microenvironment. Cell Death Dis 5:e1135. CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Vijayan D, Young A, Teng MWL, Smyth MJ (2017) Targeting immunosuppressive adenosine in cancer. Nat Rev Cancer 17(12):709–724. CrossRefPubMedGoogle Scholar
  83. 83.
    Antonioli L, Pacher P, Vizi ES, Hasko G (2013) CD39 and CD73 in immunity and inflammation. Trends Mol Med 19(6):355–367. CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    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):527–535PubMedGoogle Scholar
  85. 85.
    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. CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Di Virgilio F, Sarti AC, Falzoni S, De Marchi E, Adinolfi E (2018) Extracellular ATP and P2 purinergic signalling in the tumour microenvironment. Nat Rev Cancer. CrossRefPubMedGoogle Scholar
  87. 87.
    Tourneur L, Mistou S, Schmitt A, Chiocchia G (2008) Adenosine receptors control a new pathway of Fas-associated death domain protein expression regulation by secretion. J Biol Chem 283(26):17929–17938. CrossRefPubMedGoogle Scholar
  88. 88.
    Brose KM, Lee AY (2008) Cancer-associated thrombosis: prevention and treatment. Curr Oncol 15(Suppl 1):S58–S67CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Rothmeier AS, Marchese P, Langer F, Kamikubo Y, Schaffner F, Cantor J, Ginsberg MH, Ruggeri ZM, Ruf W (2017) Tissue factor prothrombotic activity is regulated by integrin-arf6 trafficking. Arterioscler Thromb Vasc Biol 37(7):1323–1331. CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Date K, Ettelaie C, Maraveyas A (2017) Tissue factor-bearing microparticles and inflammation: a potential mechanism for the development of venous thromboembolism in cancer. J Thromb Haemost 15(12):2289–2299. CrossRefPubMedGoogle Scholar
  91. 91.
    Crusz SM, Balkwill FR (2015) Inflammation and cancer: advances and new agents. Nat Rev Clin Oncol 12(10):584–596. CrossRefPubMedGoogle Scholar
  92. 92.
    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. CrossRefPubMedGoogle Scholar
  93. 93.
    Morelli A, Chiozzi P, Chiesa A, Ferrari D, Sanz JM, Falzoni S, Pinton P, Rizzuto R, Olson MF, Di Virgilio F (2003) Extracellular ATP causes ROCK I-dependent bleb formation in P2X7-transfected HEK293 cells. Mol Biol Cell 14(7):2655–2664. CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Pfeiffer ZA, Aga M, Prabhu U, Watters JJ, Hall DJ, Bertics PJ (2004) The nucleotide receptor P2X7 mediates actin reorganization and membrane blebbing in RAW 264.7 macrophages via p38 MAP kinase and Rho. J Leukoc Biol 75(6):1173–1182. CrossRefPubMedGoogle Scholar
  95. 95.
    Panupinthu N, Zhao L, Possmayer F, Ke HZ, Sims SM, Dixon SJ (2007) P2X7 nucleotide receptors mediate blebbing in osteoblasts through a pathway involving lysophosphatidic acid. J Biol Chem 282(5):3403–3412. CrossRefPubMedGoogle Scholar
  96. 96.
    Fairbairn IP, Stober CB, Kumararatne DS, Lammas DA (2001) ATP-mediated killing of intracellular mycobacteria by macrophages is a P2X(7)-dependent process inducing bacterial death by phagosome-lysosome fusion. J Immunol 167(6):3300–3307CrossRefPubMedGoogle Scholar
  97. 97.
    Garcia-Marcos M, Dehaye JP, Marino A (2009) Membrane compartments and purinergic signalling: the role of plasma membrane microdomains in the modulation of P2XR-mediated signalling. FEBS J 276(2):330–340. CrossRefPubMedGoogle Scholar
  98. 98.
    Skotland T, Sandvig K, Llorente A (2017) Lipids in exosomes: current knowledge and the way forward. Prog Lipid Res 66:30–41. CrossRefPubMedGoogle Scholar
  99. 99.
    Ferrari D, Bianchi N, Eltzschig HK, Gambari R (2016) MicroRNAs modulate the purinergic signaling network. Trends Mol Med 22(10):905–918. CrossRefPubMedGoogle Scholar
  100. 100.
    Graner MW, Schnell S, Olin MR (2018) Tumor-derived exosomes, microRNAs, and cancer immune suppression. Semin Immunopathol.
  101. 101.
    Moore C, Kosgodage U, Lange S, Inal JM (2017) The emerging role of exosome and microvesicle- (EMV-) based cancer therapeutics and immunotherapy. Int J Cancer 141(3):428–436. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeurosurgeryUniversity of Colorado Denver, Anschutz Medical CampusAuroraUSA

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