Immune Modulation of T Cells and Natural Killer Cells by Tumor-Derived Exosomes

Chapter

Abstract

Tumor-derived exosomes (TEX) are present in body fluids of patients with cancer. By downregulating functions of immune cells, TEX promote tumor progression. In patients with cancer, apoptosis of activated tumor-specific T cells, depressed natural killer (NK) cell activity, and the increased frequency in the peripheral blood or tumor sites of CD4+CD25hiFOXP3+ regulatory T cells (Treg) are common and consistent findings. Evidence suggests that TEX have immunoregulatory properties and contribute to CD8+ effector T cell apoptosis, induction/expansion of Treg, and inhibition of NK cell activity. Membrane-associated molecules, such as TGF-b or Fas ligand, are carried by TEX and are responsible for the ability of TEX to regulate peripheral tolerance in patients with cancer.

Keywords

Tumor-derived exosomes Tumor escape Immunosuppression T cells NK cells 

References

  1. 1.
    Whiteside TL, Mandapathil M, Szczepanski M, Szajnik M (2011) Mechanisms of tumor escape from the immune system: adenosine-producing Treg, exosomes and tumor-associated TLRs. Bull Cancer 98:E25–E31PubMedGoogle Scholar
  2. 2.
    Whiteside TL (2006) Immune suppression in cancer: effects on immune cells, mechanisms and future therapeutic intervention. Sem Cancer Biol 16:3–15CrossRefGoogle Scholar
  3. 3.
    Huber V, Fais S, Iero M, Lugini L, Canese P, Squarcina P, Zaccheddu A, Colone M, Arancia G, Gentile M, Seregni E, Valenti R, Ballabio G, Belli F, Leo E, Parmiani G, Rivoltini L (2005) Human colorectal cancer cells induce T-cell death through release of proapoptotic microvesicles: role in immune escape. Gastroenterology 128:1796–1804PubMedCrossRefGoogle Scholar
  4. 4.
    Kim J-W, Wieckowski E, Taylor DD, Reichert TE, Watkins S, Whiteside TL (2005) FasL + membraneous vesicles isolated from sera of patients with oral cancer induce apoptosis of activated T lymphocytes. Clin Cancer Res 11:1010–1020PubMedGoogle Scholar
  5. 5.
    Taylor DD, Gercel-Taylor C (2005) Tumour-derived exosomes and their role in cancer-associated T-cell signaling defects. Br J Cancer 92:305–311PubMedGoogle Scholar
  6. 6.
    Taylor DD, Gercel-Taylor C, Lyons KS, Stanson J, Whiteside TL (2003) T-cell apoptosis and suppression of T-cell receptor/CD3-zeta by Fas ligand-containing membrane vesicles shed from ovarian tumors. Clin Cancer Res 9:5113–5119PubMedGoogle Scholar
  7. 7.
    Chaput N, Thery C (2011) Exosomes: immune properties and potential clinical implementations. Semin Immunopathol 33:419–440PubMedCrossRefGoogle Scholar
  8. 8.
    Bobrie A, Colombo M, Raposo G, Thery C (2011) Exosome secretion: molecular mechanisms and roles in immune responses. Traffic. doi:10.1111/j.1600–0854.2011.01225Google Scholar
  9. 9.
    Thery C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev 2:569–579Google Scholar
  10. 10.
    Wieckowski E, Whiteside TL (2006) Human tumor-derived vs. dendritic cell-derived exosomes have distinct biologic roles and molecular profiles. Immunol Res 36:247–254PubMedCrossRefGoogle Scholar
  11. 11.
    Clayton A, Court J, Navabi H, Adams M, Mason MD, Hobot JA, Newman GR, Jasani B (2001) Analysis of antigen presenting cell derived exosomes, based on immuno-magnetic isolation and flow cytometry. J Immunol Meth 247:163–174CrossRefGoogle Scholar
  12. 12.
    Thery C, Regnault A, Garin J, Wolfers J, Zitvogel L, Ricciardi-Castagnoli P, Raposo G, Amigorena S (1999) Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. J cell Biol 147:599–610PubMedCrossRefGoogle Scholar
  13. 13.
    Andreola G, Rivoltini L, Castelli C, Huber V, Perego P, Deho P, Squarcina P, Accornero P, Lozupone F, Lugini L, Stringaro A, Molinari A, Arancia G, Gentile M, Parmiani G, Fais S (2002) Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. J Exp Med 195:1303–1316PubMedCrossRefGoogle Scholar
  14. 14.
    Andre F, Schartz NE, Chaput N, Flament C, Raposo G, Amigorena S, Angevin E, Zitvogel L (2002) Tumor-derived exosomes: a new source of tumor rejection antigens. Vaccine 20 Suppl 4:A28–31CrossRefGoogle Scholar
  15. 15.
    Wolfers J, Lozier A, Raposo G, Regnault A, Thery C, Masurier C, Flament C, Pouzieux S, Faure F, Tursez 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 7:297–303PubMedCrossRefGoogle Scholar
  16. 16.
    Thery C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9:581–593PubMedCrossRefGoogle Scholar
  17. 17.
    Mathivanan S, Lim JW, Tauro BJ, Ji H, Moritz RL, Simpson RJ (2010) Proteomics analysis of A33 immunoaffinity-purified exosomes released from the human colon tumor cell line LIM1215 reveals a tissue-specific protein signature. Mol Cell Proteomics 9:197–208PubMedCrossRefGoogle Scholar
  18. 18.
    Hegmans JP, Bard MP, Hemmes A, Luider TM, Kleijmeer MJ, Prins JB, Zitvogel L, Burgers SA, Hoogsteden HC, Lambrecht BN (2004) Proteomic analysis of exosomes secreted by human mesothelioma cells. Am J Path 164:1807–1815PubMedCrossRefGoogle Scholar
  19. 19.
    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 187:676–683PubMedCrossRefGoogle Scholar
  20. 20.
    Wieckowski E, Visus C, Szajnik M, Szczepanski MJ, Storkus WJ, Whiteside TL (2009) Tumor-derived microvesicles promote regulatory T-cell expansion and induce apoptosis in tumor-reactive activated CD8 + T lymphoctyes. J Immunol 183:3720–30PubMedCrossRefGoogle Scholar
  21. 21.
    Gastpar R, Gehemann M, Bausero MA, Asea A, Gross C, Schroeder JA, Multhoff G (2005) Heat shock protein 70 surface-positive exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res 65:5238–5247PubMedCrossRefGoogle Scholar
  22. 22.
    Andre F, Chaput N, Schartz NE, Flament C, Aubert N, Bernard J, Lemonnier F, Raposo G, Escudier B, Hsu DH, Tursz T, Amigorena S, Angevin E, Zitvogel L (2004) Exosomes as potent cell-free peptide-based vaccine. I. Dendritic cell-derived exosomes transfer functional MHC class I/peptide complexes to dendritic cells. J Immunol 172:2126–2136Google Scholar
  23. 23.
    Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, Ricciardi-Castagnoli P, Raposo G, Amigorena S (1998) Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med 4:594–600PubMedCrossRefGoogle Scholar
  24. 24.
    Chaput N, Schartz NE, Andre F, Zitvogel L (2003) Exosomes for immunotherapy of cancer. Adv Exp Med Biol 532:215–221PubMedCrossRefGoogle Scholar
  25. 25.
    Viaud S, Thery C, Ploix S, Tursz T, Lapierre V, Lanz O, Zitrogel L, Chaput N (2010) Dendritic-cell derived exosomes for cancer immunotherapy: what’s next? Cancer Res 70:1281–1285PubMedCrossRefGoogle Scholar
  26. 26.
    Hoffmann TK, Dworacki G, Meidenbauer N, Gooding W, Johnson JT, Whiteside TL (2002) Spontaneous apoptosis of circulating T lymphocytes in patients with head and neck cancer and its clinical importance. Clin Cancer Res 8:2553–2562PubMedGoogle Scholar
  27. 27.
    Reichert TE, Strauss L, Wagner EM, Gooding W, Whiteside TL (2002) Signaling abnormalities and reduced proliferation of circulating and tumor-infiltrating lymphocytes in patients with oral carcinoma. Clin Cancer Res 8:3137–3145PubMedGoogle Scholar
  28. 28.
    Kim J-W, Tsukishiro T, Johnson JT, Whiteside TL (2004) Expression of pro- and anti-apoptotic proteins in circulating CD8 + T cells of patients with squamous cell carcinoma of the head and neck (SCCHN). Clin Cancer Res 10:5101–5110PubMedCrossRefGoogle Scholar
  29. 29.
    Saito T, Kuss I, Dworacki G, Gooding W, Johnson JT, Whiteside TL (1999) Spontaneous ex vivo apoptosis of peripheral blood mononuclear cells in patients with head and neck cancer. Clin Cancer Res 5:1263–1273PubMedGoogle Scholar
  30. 30.
    Whiteside TL (2002) Tumor-induced death of immune cells: its mechanisms and consequences. Sem Cancer Biol 12:43–50CrossRefGoogle Scholar
  31. 31.
    Saito T, Dworacki G, Gooding W, Lotze MT, Whiteside TL (2000) Spontaneous apoptosis of CD8 + T lymphocytes in peripheral blood of patients with advanced melanoma. Clin Cancer Res 6:1351–1364PubMedGoogle Scholar
  32. 32.
    Martinez-Lorenzo MJ, Anel A, Alava MA, Pineiro A, Naval J, Lasierra P, Larrad L (2004) The human melanoma cell line MelJuSo secretes bioactive FasL and APO2 L/TRAIL on the surface of microvesicles. Possible contribution to tumor counterattack. Exp Cell Res 295:315–329PubMedCrossRefGoogle Scholar
  33. 33.
    Abrahams VM, Straszewski SL, Kamsteeg M, Hanczaruk B, Schwartz PE, Rutherford TJ, Mor G (2003) Epithelial ovarian cancer cells secrete functional Fas ligand. Cancer Res 63:5573–5581PubMedGoogle Scholar
  34. 34.
    Contini P, Ghio M, Poggi A, Filaci G, Indiveri F, Ferrone S, Puppo F (2003) Soluble HLA-A,-B,-C and -G molecules induce apoptosis in T and NK CD8 + cells and inhibit cytotoxic T cell activity through CD8 ligation. Eur J Immunol 33:125–134PubMedCrossRefGoogle Scholar
  35. 35.
    Contini P, Ghio M, Merlo A, Poggi A, Indiveri F, Puppo F (2005) Apoptosis of antigen-specific T lymphocytes upon the engagement of CD8 by soluble HLA class I molecules is Fas ligand/Fas mediated: evidence for the involvement of p56lck, calcium calmodulin kinase II, and Calcium-independent protein kinase C signaling pathways and for NF-kappaB and NF-AT nuclear translocation. J Immunol 175:7244–7254PubMedGoogle Scholar
  36. 36.
    Whiteside TL (2004) Down-regulation of zeta-chain expression in T cells: a biomarker of prognosis in cancer? Cancer Immunol Immunother 53:865–878PubMedGoogle Scholar
  37. 37.
    Reichert TE, Day R, Wagner EM, Whiteside TL (1998) Absent or low expression of the  z chain in T cells at the tumor site correlates with poor survival in patients with oral carcinoma. Cancer Res 58:5344–5347PubMedGoogle Scholar
  38. 38.
    Taylor DD, Akyol S, Gercel-Taylor C (2006) Pregnancy-associated exosomes and their modulation of T cell signaling. J Immunol 176:1534–1542PubMedGoogle Scholar
  39. 39.
    Sabapatha A, Gercel-Taylor C, Taylor DD (2006) Specific isolation of placenta-derived exosomes from the circulation of pregnant women and their immunoregulatory consequences. Am J Reprod Immunol 56:345–355PubMedCrossRefGoogle Scholar
  40. 40.
    Clayton A, Mitchell JP, Court J, Mason MD, Tabi Z (2007) Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res 67:7458–7466PubMedCrossRefGoogle Scholar
  41. 41.
    Valenti R, Huber V, Filipazzi P, Pilla L, Sovena G, Villa A, Corbelli A, Fais S, Parmiani G, Rivoltini L (2006) Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor beta-mediated suppressive activity on T lymphocytes. Cancer Res 66:9290–9298PubMedCrossRefGoogle Scholar
  42. 42.
    Czystowska M, Han J, Szczepanski MJ, Szajnik M, Quadrini K, Brandwein H, Hadden JW, Signorelli K, Whiteside TL (2009) IRX-2, a novel immunotherapeutic, protects human T cells from tumor-induced cell death. Cell Death Diff 16:708–718CrossRefGoogle Scholar
  43. 43.
    Czystowska M, Szczepanski MJ, Szajnik M, Quadrini K, Brandwein H, Hadden JW, Whiteside TL (2011) Mechanisms of T-cell protection from death by IRX-2, a new immunotherapeutic. Cancer Immunol Immunother 60:495–506PubMedCrossRefGoogle Scholar
  44. 44.
    Groneberg C, Pickartz T, Binder A, Ringel R, Srock S, Sieber T, Schoeler D, Schriever F (2003) Clinical relevance of CD95 (Fas/Apo-1) on T cells of patients with B-cell chronic lymphocytic leukemia. Exp Hematol 31:682–685PubMedCrossRefGoogle Scholar
  45. 45.
    Massaia M, Borrione P, Attisano C, Barral P, Beggiato E, Montacchini L, Bianchi A, Boccadoro M, Pileri A (1995) Dysregulated Fas and Bcl-2 expression leading to enhanced apoptosis in T cells of multiple myeloma patients. Blood 85:3679–3687PubMedGoogle Scholar
  46. 46.
    Ghosh AK, Secreto CR, Knox TR, Ding W, Mukhopadhyay D, Kay NE (2010) Circulating microvesicles in B-cell chronic lymphocytic leukemia can stimulate marrow stromal cells: implications for disease progression. Blood 115:1755–1764PubMedCrossRefGoogle Scholar
  47. 47.
    Szajnik M, Czystowska M, Szczepanski MJ, Mandapathil M, Whiteside TL (2010) Tumor-derived microvesicles induce, expand and up-regulate biological activities of human regulatory T cells (Treg). PLoS ONE 5:e11469Google Scholar
  48. 48.
    Bauernhofer T, Kuss I, Henderson B, Baum AS, Whiteside TL (2003) Preferential apoptosis of CD56dim natural killer cell subset in patients with cancer. Eur J Immunol 33:19–124CrossRefGoogle Scholar
  49. 49.
    Szczepanski MJ, Szajnik M, Welsh A, Foon KA, Whiteside TL, Boyiadzis M (2010) Interleukin-15 enhances NK cell cytotoxicity in patients with acute myeloid leukemia by upregulating the activating NK cell receptors. Cancer Immunol Immunother 59:73–79PubMedCrossRefGoogle Scholar
  50. 50.
    Liu C, Yu S, Zinn K, Wang J, Zhang L, Jia Y, Kappes JC, Barnes S, Kimberly RP, Grizzle WE, Zhang HG (2006) Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. J Immunol 176:1375–1385PubMedGoogle Scholar
  51. 51.
    Clayton A, Mitchell JP, Court J, Linnane S, Mason MD, Tabi Z (2008) Human tumor-derived exosomes down-modulate NKG2D expression. J Immunol 180:7249–7258PubMedGoogle Scholar
  52. 52.
    Clayton A, Tabi Z (2005) Exosomes and the MICA-NKG2D system in cancer. Blood Cells Mol Dis 34:206–213PubMedCrossRefGoogle Scholar
  53. 53.
    Lee J-C, Lee K-M, Kim W-D, Heo DS (2004) Elevated TGF- ß1 secretion and down-modulation of NK62D underlies impaired NK cytotoxicity in cancer patients. J Immunol 172:7335–7340PubMedGoogle Scholar
  54. 54.
    Szczepanski MJ, Szajnik M, Welsh A, Whiteside TL, Boyiadzis M (2011) Blast-derived microvesicles in sera of acute myeloid leukemia patients suppresses NK cell function via membrane-associated TGF-ß1. Haematologica 96:1302–1309PubMedCrossRefGoogle Scholar
  55. 55.
    Zhang H, Conrad DM, Butler JJ, Zhao C, Blay J, Hoskin DW (2004) Adenosine acts through A2 receptors to inhibit IL-2-induced tyrosine phosphorylation of STAT5 in T lymphocytes: role of cyclic adenosine 3’5’-monophosphate and phosphatases. J Immunol 173:932–944PubMedGoogle Scholar
  56. 56.
    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 204:1257–1265PubMedCrossRefGoogle Scholar
  57. 57.
    Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, Hopner S, Centonze D, Bernardi G, Dell’Acqua ML, Rossini PM, Battistini L, Rotzschke O, Falk K (2007) Expression of ectonucleotidase CD39 by Foxp3 + Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110:1225–1232PubMedCrossRefGoogle Scholar
  58. 58.
    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 285:27571–27580PubMedCrossRefGoogle Scholar
  59. 59.
    Zhang B (2010) CD73: A novel target for cancer immunotherapy. Cancer Res 70:6407–6411PubMedCrossRefGoogle Scholar
  60. 60.
    Bergman C, Strauss L, Wieckowski E, Czystowska M, Albers A, Wang Y, Zeidler R, Lang S, Whiteside TL (2008) Tumor-derived microvesicles in sera of patients with head and neck cancer and their role in tumor progression. Head Neck 31:371–380CrossRefGoogle Scholar
  61. 61.
    Battke C, Ruiss R, Welsch U, Wimberger P, Lang S, Jochum S, Zeidler R (2011) Tumour exosomes inhibit binding of tumour-reactive antibodies to tumour cells and reduce ADCC. Cancer Immunol Immunother 60:639–648PubMedCrossRefGoogle Scholar
  62. 62.
    Iero M, Valenti R, Huber V, Filipazzi P, Parmiani G, Fais S, Rivoltini L (2008) Tumour-released exosomes and their implications in cancer immunity. Cell Death Diff 15:80–88CrossRefGoogle Scholar
  63. 63.
    Ichim TE, Zhong Z, Kaushal S, Zheng X, Ren X, Hao X, Joyce JA, Hanley HH, Riordan NH, Koropatnick J, Bogin V, Minev BR, Min WP, Tullis RH (2008) Exosomes as a tumor immune escape mechanism: possible therapeutic implications. J Transl Med 6:37PubMedCrossRefGoogle Scholar
  64. 64.
    Huber V, Filipazzi P, Iero M, Fais S, Rivoltini L (2008) More insights into the immunosuppressive potential of tumor exosomes. J Transl Med 6:63–66PubMedCrossRefGoogle Scholar
  65. 65.
    Smyth MJ, Cretney E, Kerskaw MH, Hakayawa Y (2004) Cytokines in cancer immunity and immunotherapy. Immunol Rev 202:275–293PubMedCrossRefGoogle Scholar
  66. 66.
    Alpizar YA, Chain B, Collins MK, Greenwood J, Katz D, Strauss HJ, Mitchison NA (2011) Ten years of progress in vaccination against cancer: the need to conunteract cancer evasion by dual targeting in future therapies. Cancer Immunol Immunother 60:1127–1135PubMedCrossRefGoogle Scholar
  67. 67.
    Baumgaertner P, Jandus C, Rivals JP, Derre L, Lovgren T, Baitsch L, Guillaum P, Luescher IF, Berthod G, Matter M, Rufer N, Michielin O, Speiser DE (2011) Vaccination-induced functional competence of circulating human tumor-specific CD8 T-cells. Int J Cancer doi:10.1002/ijc.26297Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.University of Pittsburgh Cancer InstitutePittsburghUSA

Personalised recommendations