Skip to main content

Advertisement

SpringerLink
Log in

Tumor-derived exosomes, microRNAs, and cancer immune suppression

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Originally considered to be part of a cellular waste pathway, expansive research into exosomes has shown that these vesicles possess a vast array of functional utilities. As vital transporters of materials for communications between cells, particular interest has been generated in the ability of cancer cells to use exosomes to induce immune suppression, and to establish a thriving microenvironment, ideal for disease progression. Exosomes carry and transfer many types of cargo, including microRNAs (miRNAs; miRs), which are important modulators of messenger RNA (mRNA) expression. These miRNAs have been shown to be noteworthy components of the mechanisms used by tumor-derived exosomes to carry out their functions. Alternatively, research has been expanding into using exosomes and miRNAs as both biomarkers for detecting cancer and disease progression, and as potential treatment tools. Here, we discuss some of the progress that researchers have made related to cancer exosomes, their suppression of the immune system and the importance of the miRNAs they shuttle, along with some of the shortcomings, obstacles, and challenges that lie ahead.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Kalluri R (2016) The biology and function of exosomes in cancer. J Clin Invest 126:1208–1215

    PubMed  PubMed Central  Google Scholar 

  2. 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

    PubMed  Google Scholar 

  3. Szatanek R, Baran J, Siedlar M, Baj-Krzyworzeka M (2015) Isolation of extracellular vesicles: determining the correct approach (review). Int J Mol Med 36:11–17

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Wolf P (1967) The nature and significance of platelet products in human plasma. Br J Haematol 13:269–288

    CAS  PubMed  Google Scholar 

  5. Anderson HC (1969) Vesicles associated with calcification in the matrix of epiphyseal cartilage. J Cell Biol 41:59–72

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Harding C, Heuser J, Stahl P (1983) Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol 97:329–339

    CAS  PubMed  Google Scholar 

  7. Pan BT, Teng K, Wu C, Adam M, Johnstone RM (1985) Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J Cell Biol 101:942–948

    CAS  PubMed  Google Scholar 

  8. 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 262:9412–9420

    CAS  PubMed  Google Scholar 

  9. 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

    PubMed  PubMed Central  Google Scholar 

  10. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, Geuze HJ (1996) B lymphocytes secrete antigen-presenting vesicles. J Exp Med 183:1161–1172

    CAS  PubMed  Google Scholar 

  11. 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 4:594–600

    CAS  PubMed  Google Scholar 

  12. Kunigelis KE, Graner MW (2015) The dichotomy of tumor exosomes (TEX) in cancer immunity: is it all in the ConTEXt? Vaccines (Basel) 3:1019–1051

    CAS  Google Scholar 

  13. 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 16:782–790

    CAS  PubMed  Google Scholar 

  14. Robbins PD, Morelli AE (2014) Regulation of immune responses by extracellular vesicles. Nat Rev Immunol 14:195–208

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 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

    CAS  PubMed  Google Scholar 

  16. Meehan K, Vella LJ (2016) The contribution of tumour-derived exosomes to the hallmarks of cancer. Crit Rev Clin Lab Sci 53:121–131

    CAS  PubMed  Google Scholar 

  17. Hellwinkel JE, Redzic JS, Harland TA, Gunaydin D, Anchordoquy TJ, Graner MW (2015) Glioma-derived extracellular vesicles selectively suppress immune responses. Neuro-Oncology

  18. Wendler F, Stamp GW, Giamas G (2016) Tumor-stromal cell communication: small vesicles signal big changes. Trends Cancer 2:326–329

    PubMed  Google Scholar 

  19. C RG, Bernard G, Tremblay S, Chabaud S, Bolduc S, Pouliot F. 2018. Exosomes induce fibroblast differentiation into cancer-associated fibroblasts through TGFbeta signaling. Mol Cancer res

  20. Oushy S, Hellwinkel JE, Wang M, Nguyen GJ, Gunaydin D, Harland TA, Anchordoquy TJ, Graner MW (2018) Glioblastoma multiforme-derived extracellular vesicles drive normal astrocytes towards a tumour-enhancing phenotype. Philos Trans R Soc Lond Ser B Biol Sci 373:20160477

    Google Scholar 

  21. 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 195:1303–1316

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659

    CAS  PubMed  Google Scholar 

  23. Ung TH, Madsen HJ, Hellwinkel JE, Lencioni AM, Graner MW (2014) Exosome proteomics reveals transcriptional regulator proteins with potential to mediate downstream pathways. Cancer Sci 105:1384–1392

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, Rak J (2008) Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 10:619–624

    CAS  PubMed  Google Scholar 

  25. Mu W, Rana S, Zoller M (2013) Host matrix modulation by tumor exosomes promotes motility and invasiveness. Neoplasia 15:875–887

    PubMed  PubMed Central  Google Scholar 

  26. Sung BH, Ketova T, Hoshino D, Zijlstra A, Weaver AM (2015) Directional cell movement through tissues is controlled by exosome secretion. Nat Commun 6:7164

    CAS  PubMed  Google Scholar 

  27. Vivier E, Tomasello E, Paul P (2002) Lymphocyte activation via NKG2D: towards a new paradigm in immune recognition? Curr Opin Immunol 14:306–311

    CAS  PubMed  Google Scholar 

  28. Chitadze G, Bhat J, Lettau M, Janssen O, Kabelitz D (2013) Generation of soluble NKG2D ligands: proteolytic cleavage, exosome secretion and functional implications. Scand J Immunol 78:120–129

    CAS  PubMed  Google Scholar 

  29. Gross C, Hansch D, Gastpar R, Multhoff G (2003) Interaction of heat shock protein 70 peptide with NK cells involves the NK receptor CD94. Biol Chem 384:267–279

    CAS  PubMed  Google Scholar 

  30. Mincheva-Nilsson L, Baranov V (2014) Cancer exosomes and NKG2D receptor-ligand interactions: impairing NKG2D-mediated cytotoxicity and anti-tumour immune surveillance. Semin Cancer Biol 28:24–30

    CAS  PubMed  Google Scholar 

  31. Clayton A, Tabi Z (2005) Exosomes and the MICA-NKG2D system in cancer. Blood Cells Mol Dis 34:206–213

    CAS  PubMed  Google Scholar 

  32. Hedlund M, Nagaeva O, Kargl D, Baranov V, Mincheva-Nilsson L (2011) Thermal- and oxidative stress causes enhanced release of NKG2D ligand-bearing immunosuppressive exosomes in leukemia/lymphoma T and B cells. PLoS One 6:e16899

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 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 23:1541–1557

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Szczepanski MJ, Szajnik M, Welsh A, Whiteside TL, Boyiadzis M (2011) Blast-derived microvesicles in sera from patients with acute myeloid leukemia suppress natural killer cell function via membrane-associated transforming growth factor-beta1. Haematologica 96:1302–1309

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 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 6:37

    PubMed  PubMed Central  Google Scholar 

  36. 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 187:676–683

    CAS  PubMed  Google Scholar 

  37. Allard B, Longhi MS, Robson SC, Stagg J (2017) The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol Rev 276:121–144

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Spychala J (2000) Tumor-promoting functions of adenosine. Pharmacol Ther 87:161–173

    CAS  PubMed  Google Scholar 

  39. 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:e11469

    PubMed  PubMed Central  Google Scholar 

  40. Clayton A, Mason MD (2009) Exosomes in tumour immunity. Curr Oncol 16:46–49

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Salimu J, Webber J, Gurney M, Al-Taei S, Clayton A, Tabi Z (2017) Dominant immunosuppression of dendritic cell function by prostate-cancer-derived exosomes. J Extracell Vesicles 6:1368823

    PubMed  PubMed Central  Google Scholar 

  42. Valenti R, Huber V, Iero M, Filipazzi P, Parmiani G, Rivoltini L (2007) Tumor-released microvesicles as vehicles of immunosuppression. Cancer Res 67:2912–2915

    CAS  PubMed  Google Scholar 

  43. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, Garcia-Santos G, Ghajar C, Nitadori-Hoshino A, Hoffman C, Badal K, Garcia BA, Callahan MK, Yuan J, Martins VR, Skog J, Kaplan RN, Brady MS, Wolchok JD, Chapman PB, Kang Y, Bromberg J, Lyden D (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18:883–891

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Rutkowski MR, Svoronos N, Perales-Puchalt A, Conejo-Garcia JR (2015) The tumor macroenvironment: cancer-promoting networks beyond tumor beds. Adv Cancer Res 128:235–262

    PubMed  PubMed Central  Google Scholar 

  45. de Vrij J, Maas SL, Kwappenberg KM, Schnoor R, Kleijn A, Dekker L, Luider TM, de Witte LD, Litjens M, van Strien ME, Hol EM, Kroonen J, Robe PA, Lamfers ML, Schilham MW, Broekman ML (2015) Glioblastoma-derived extracellular vesicles modify the phenotype of monocytic cells. Int J Cancer 137:1630–1642

    PubMed  Google Scholar 

  46. Bardi GT, Smith MA, Hood JL (2018) Melanoma exosomes promote mixed M1 and M2 macrophage polarization. Cytokine 105:63–72

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Whiteside TL (2017) Exosomes carrying immunoinhibitory proteins and their role in cancer. Clin Exp Immunol 189:259–267

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Salehi M, Sharifi M (2018) Exosomal miRNAs as novel cancer biomarkers: challenges and opportunities. J Cell Physiol

  49. Di Leva G, Garofalo M, Croce CM (2014) MicroRNAs in cancer. Annu Rev Pathol 9:287–314

    PubMed  Google Scholar 

  50. Ragusa M, Barbagallo C, Cirnigliaro M, Battaglia R, Brex D, Caponnetto A, Barbagallo D, Di Pietro C, Purrello M (2017) Asymmetric RNA distribution among cells and their secreted exosomes: biomedical meaning and considerations on diagnostic applications. Front Mol Biosci 4:66

    PubMed  PubMed Central  Google Scholar 

  51. Villarroya-Beltri C, Gutierrez-Vazquez C, Sanchez-Cabo F, Perez-Hernandez D, Vazquez J, Martin-Cofreces N, Martinez-Herrera DJ, Pascual-Montano A, Mittelbrunn M, Sanchez-Madrid F (2013) Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun 4:2980

    PubMed  Google Scholar 

  52. Janas T, Janas MM, Sapon K, Janas T (2015) Mechanisms of RNA loading into exosomes. FEBS Lett 589:1391–1398

    CAS  PubMed  Google Scholar 

  53. Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y, Ochiya T (2010) Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem 285:17442–17452

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Koppers-Lalic D, Hackenberg M, Bijnsdorp IV, van Eijndhoven MAJ , Sadek P, Sie D, Zini N, Middeldorp JM, Ylstra B, de Menezes RX, Wurdinger T, Meijer GA, Pegtel DM. 2014. Nontemplated nucleotide additions distinguish the small RNA composition in cells from exosomes. Cell Rep 8: 1649–1658

    CAS  PubMed  Google Scholar 

  55. Bang C, Batkai S, Dangwal S, Gupta SK, Foinquinos A, Holzmann A, Just A, Remke J, Zimmer K, Zeug A, Ponimaskin E, Schmiedl A, Yin X, Mayr M, Halder R, Fischer A, Engelhardt S, Wei Y, Schober A, Fiedler J, Thum T (2014) Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J Clin Invest 124:2136–2146

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Santangelo L, Giurato G, Cicchini C, Montaldo C, Mancone C, Tarallo R, Battistelli C, Alonzi T, Weisz A, Tripodi M (2016) The RNA-binding protein SYNCRIP is a component of the hepatocyte Exosomal machinery controlling MicroRNA sorting. Cell Rep 17:799–808

    CAS  PubMed  Google Scholar 

  57. Tkach M, Thery C (2016) Communication by extracellular vesicles: where we are and where we need to go. Cell 164:1226–1232

    CAS  PubMed  Google Scholar 

  58. Becker A, Thakur BK, Weiss JM, Kim HS, Peinado H, Lyden D (2016) Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell 30:836–848

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Umezu T, Ohyashiki K, Kuroda M, Ohyashiki JH (2013) Leukemia cell to endothelial cell communication via exosomal miRNAs. Oncogene 32:2747–2755

    CAS  PubMed  Google Scholar 

  60. Tadokoro H, Umezu T, Ohyashiki K, Hirano T, Ohyashiki JH (2013) Exosomes derived from hypoxic leukemia cells enhance tube formation in endothelial cells. J Biol Chem 288:34343–34351

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Umezu T, Tadokoro H, Azuma K, Yoshizawa S, Ohyashiki K, Ohyashiki JH (2014) Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1. Blood 124:3748–3757

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Ostenfeld MS, Jeppesen DK, Laurberg JR, Boysen AT, Bramsen JB, Primdal-Bengtson B, Hendrix A, Lamy P, Dagnaes-Hansen F, Rasmussen MH, Bui KH, Fristrup N, Christensen EI, Nordentoft I, Morth JP, Jensen JB, Pedersen JS, Beck M, Theodorescu D, Borre M, Howard KA, Dyrskjot L, Orntoft TF (2014) Cellular disposal of miR23b by RAB27-dependent exosome release is linked to acquisition of metastatic properties. Cancer Res 74:5758–5771

    CAS  PubMed  Google Scholar 

  63. Melo SA, Sugimoto H, O'Connell JT, Kato N, Villanueva A, Vidal A, Qiu L, Vitkin E, Perelman LT, Melo CA, Lucci A, Ivan C, Calin GA, Kalluri R (2014) Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 26:707–721

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Berchem G, Noman MZ, Bosseler M, Paggetti J, Baconnais S, Le Cam E, Nanbakhsh A, Moussay E, Mami-Chouaib F, Janji B, Chouaib S (2016) Hypoxic tumor-derived microvesicles negatively regulate NK cell function by a mechanism involving TGF-beta and miR23a transfer. Oncoimmunology 5:e1062968

    PubMed  Google Scholar 

  65. Cohnen A, Chiang SC, Stojanovic A, Schmidt H, Claus M, Saftig P, Janssen O, Cerwenka A, Bryceson YT, Watzl C (2013) Surface CD107a/LAMP-1 protects natural killer cells from degranulation-associated damage. Blood 122:1411–1418

    CAS  PubMed  Google Scholar 

  66. Ni F, Gui Z, Guo Q, Hu Z, Wang X, Chen D, Wang S (2016) Downregulation of miR-362-5p inhibits proliferation, migration and invasion of human breast cancer MCF7 cells. Oncol Lett 11:1155–1160

    CAS  PubMed  Google Scholar 

  67. Wu K, Yang L, Chen J, Zhao H, Wang J, Xu S, Huang Z (2015) miR-362-5p inhibits proliferation and migration of neuroblastoma cells by targeting phosphatidylinositol 3-kinase-C2beta. FEBS Lett 589:1911–1919

    CAS  PubMed  Google Scholar 

  68. Yang P, Ni F, Deng RQ, Qiang G, Zhao H, Yang MZ, Wang XY, Xu YZ, Chen L, Chen DL, Chen ZJ, Kan LX, Wang SY (2015) MiR-362-5p promotes the malignancy of chronic myelocytic leukaemia via down-regulation of GADD45alpha. Mol Cancer 14:190

    PubMed  PubMed Central  Google Scholar 

  69. Ni F, Guo C, Sun R, Fu B, Yang Y, Wu L, Ren S, Tian Z, Wei H (2015) MicroRNA transcriptomes of distinct human NK cell populations identify miR-362-5p as an essential regulator of NK cell function. Sci Rep 5:9993

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Shifrin N, Raulet DH, Ardolino M (2014) NK cell self tolerance, responsiveness and missing self recognition. Semin Immunol 26:138–144

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Ye SB, Li ZL, Luo DH, Huang BJ, Chen YS, Zhang XS, Cui J, Zeng YX, Li J (2014) Tumor-derived exosomes promote tumor progression and T-cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma. Oncotarget 5:5439–5452

    PubMed  PubMed Central  Google Scholar 

  72. Walsh PT, Buckler JL, Zhang J, Gelman AE, Dalton NM, Taylor DK, Bensinger SJ, Hancock WW, Turka LA (2006) PTEN inhibits IL-2 receptor-mediated expansion of CD4+ CD25+ Tregs. J Clin Invest 116:2521–2531

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Sharma MD, Shinde R, McGaha TL, Huang L, Holmgaard RB, Wolchok JD, Mautino MR, Celis E, Sharpe AH, Francisco LM, Powell JD, Yagita H, Mellor AL, Blazar BR, Munn DH (2015) The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment. Sci Adv 1:e1500845

    PubMed  PubMed Central  Google Scholar 

  74. Shrestha S, Yang K, Guy C, Vogel P, Neale G, Chi H (2015) Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat Immunol 16:178–187

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Ding G, Zhou L, Qian Y, Fu M, Chen J, Chen J, Xiang J, Wu Z, Jiang G, Cao L (2015) Pancreatic cancer-derived exosomes transfer miRNAs to dendritic cells and inhibit RFXAP expression via miR-212-3p. Oncotarget 6:29877–29888

    PubMed  PubMed Central  Google Scholar 

  76. Zhou M, Chen J, Zhou L, Chen W, Ding G, Cao L (2014) Pancreatic cancer derived exosomes regulate the expression of TLR4 in dendritic cells via miR-203. Cell Immunol 292:65–69

    CAS  PubMed  Google Scholar 

  77. Lin EY, Pollard JW (2004) Macrophages: modulators of breast cancer progression. Novartis Found Symp 256:158–168 discussion 68–72, 259–69

    CAS  PubMed  Google Scholar 

  78. Szebeni GJ, Vizler C, Kitajka K, Puskas LG (2017) Inflammation and cancer: extra- and intracellular determinants of tumor-associated macrophages as tumor promoters. Mediat Inflamm 2017:9294018

    Google Scholar 

  79. Fabbri M, Paone A, Calore F, Galli R, Gaudio E, Santhanam R, Lovat F, Fadda P, Mao C, Nuovo GJ, Zanesi N, Crawford M, Ozer GH, Wernicke D, Alder H, Caligiuri MA, Nana-Sinkam P, Perrotti D, Croce CM (2012) MicroRNAs bind to toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A 109:E2110–E2116

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Cervantes JL, Weinerman B, Basole C, Salazar JC (2012) TLR8: the forgotten relative revindicated. Cell Mol Immunol 9:434–438

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Challagundla KB, Wise PM, Neviani P, Chava H, Murtadha M, Xu T, Kennedy R, Ivan C, Zhang X, Vannini I, Fanini F, Amadori D, Calin GA, Hadjidaniel M, Shimada H, Jong A, Seeger RC, Asgharzadeh S, Goldkorn A, Fabbri M (2015) Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy. J Natl Cancer Inst 107

  82. Guo XL, Ma NN, Zhou FG, Zhang L, Bu XX, Sun K, Song JR, Li R, Zhang BH, Wu MC, Wei LX (2009) Up-regulation of hTERT expression by low-dose cisplatin contributes to chemotherapy resistance in human hepatocellular cancer cells. Oncol Rep 22:549–556

    PubMed  Google Scholar 

  83. Jang JY, Lee JK, Jeon YK, Kim CW (2013) Exosome derived from epigallocatechin gallate treated breast cancer cells suppresses tumor growth by inhibiting tumor-associated macrophage infiltration and M2 polarization. BMC Cancer 13:421

    PubMed  PubMed Central  Google Scholar 

  84. Lawrence T (2009) The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 1:a001651

    PubMed  PubMed Central  Google Scholar 

  85. Hagemann T, Biswas SK, Lawrence T, Sica A, Lewis CE (2009) Regulation of macrophage function in tumors: the multifaceted role of NF-kappaB. Blood 113:3139–3146

    CAS  PubMed  Google Scholar 

  86. Fanini F, Fabbri M (2017) Cancer-derived exosomic microRNAs shape the immune system within the tumor microenvironment: state of the art. Semin Cell Dev Biol 67:23–28

    CAS  PubMed  Google Scholar 

  87. Eichmuller SB, Osen W, Mandelboim O, Seliger B (2017) Immune modulatory microRNAs involved in tumor attack and tumor immune escape. J Natl Cancer Inst 109

  88. Alfonsi R, Grassi L, Signore M, Bonci D (2018) The double face of exosome-carried microRNAs in cancer immunomodulation. Int J Mol Sci 19

    PubMed Central  Google Scholar 

  89. Viaud S, Terme M, Flament C, Taieb J, Andre F, Novault S, Escudier B, Robert C, Caillat-Zucman S, Tursz T, Zitvogel L, Chaput N (2009) Dendritic cell-derived exosomes promote natural killer cell activation and proliferation: a role for NKG2D ligands and IL-15Ralpha. PLoS One 4:e4942

    PubMed  PubMed Central  Google Scholar 

  90. Madhavan B, Yue S, Galli U, Rana S, Gross W, Muller M, Giese NA, Kalthoff H, Becker T, Buchler MW, Zoller M (2015) Combined evaluation of a panel of protein and miRNA serum-exosome biomarkers for pancreatic cancer diagnosis increases sensitivity and specificity. Int J Cancer 136:2616–2627

    CAS  PubMed  Google Scholar 

  91. Sugimachi K, Matsumura T, Hirata H, Uchi R, Ueda M, Ueo H, Shinden Y, Iguchi T, Eguchi H, Shirabe K, Ochiya T, Maehara Y, Mimori K (2015) Identification of a bona fide microRNA biomarker in serum exosomes that predicts hepatocellular carcinoma recurrence after liver transplantation. Br J Cancer 112:532–538

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Fong MY, Zhou W, Liu L, Alontaga AY, Chandra M, Ashby J, Chow A, O'Connor ST, Li S, Chin AR, Somlo G, Palomares M, Li Z, Tremblay JR, Tsuyada A, Sun G, Reid MA, Wu X, Swiderski P, Ren X, Shi Y, Kong M, Zhong W, Chen Y, Wang SE (2015) Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol 17:183–194

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Deng Z, Rong Y, Teng Y, Zhuang X, Samykutty A, Mu J, Zhang L, Cao P, Yan J, Miller D, Zhang HG (2017) Exosomes miR-126a released from MDSC induced by DOX treatment promotes lung metastasis. Oncogene 36:639–651

    CAS  PubMed  Google Scholar 

  94. Redzic JS, Ung TH, Graner MW (2014) Glioblastoma extracellular vesicles: reservoirs of potential biomarkers. Pharmgenomics Pers Med 7:65–77

    PubMed  PubMed Central  Google Scholar 

  95. Kai K, Dittmar RL, Sen S (2017) Secretory microRNAs as biomarkers of cancer. Semin Cell Dev Biol

  96. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29:341–345

    CAS  PubMed  Google Scholar 

  97. Ohno S, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, Fujita K, Mizutani T, Ohgi T, Ochiya T, Gotoh N, Kuroda M (2013) Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther 21:185–191

    CAS  PubMed  Google Scholar 

  98. Munoz JL, Bliss SA, Greco SJ, Ramkissoon SH, Ligon KL, Rameshwar P (2013) Delivery of functional anti-miR-9 by mesenchymal stem cell-derived exosomes to glioblastoma Multiforme cells conferred chemosensitivity. Mol Ther Nucleic Acids 2:e126

    PubMed  PubMed Central  Google Scholar 

  99. Kosaka N, Iguchi H, Yoshioka Y, Hagiwara K, Takeshita F, Ochiya T (2012) Competitive interactions of cancer cells and normal cells via secretory microRNAs. J Biol Chem 287:1397–1405

    CAS  PubMed  Google Scholar 

  100. Nguyen J, Szoka FC (2012) Nucleic acid delivery: the missing pieces of the puzzle? Acc Chem Res 45:1153–1162

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Esquela-Kerscher A, Slack FJ (2006) Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 6:259–269

    CAS  PubMed  Google Scholar 

  102. Whiteside TL (2016) Exosomes and tumor-mediated immune suppression. J Clin Invest 126:1216–1223

    PubMed  PubMed Central  Google Scholar 

  103. Puzar Dominkus P, Stenovec M, Sitar S, Lasic E, Zorec R, Plemenitas A, Zagar E, Kreft M, Lenassi M (2018) PKH26 labeling of extracellular vesicles: characterization and cellular internalization of contaminating PKH26 nanoparticles. Biochim Biophys Acta 1860:1350–1361

    CAS  Google Scholar 

  104. Wiklander OP, Nordin JZ, O'Loughlin A, Gustafsson Y, Corso G, Mager I, Vader P, Lee Y, Sork H, Seow Y, Heldring N, Alvarez-Erviti L, Smith CI, Le Blanc K, Macchiarini P, Jungebluth P, Wood MJ, Andaloussi SE (2015) Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles 4:26316

    PubMed  Google Scholar 

  105. Bahrami A, Aledavood A, Anvari K, Hassanian SM, Maftouh M, Yaghobzade A, Salarzaee O, ShahidSales S, Avan A (2018) The prognostic and therapeutic application of microRNAs in breast cancer: tissue and circulating microRNAs. J Cell Physiol 233:774–786

    CAS  PubMed  Google Scholar 

  106. Fabbri M (2018) MicroRNAs and miRceptors: a new mechanism of action for intercellular communication. Philos Trans R Soc Lond Ser B Biol Sci 373:20160486

    Google Scholar 

  107. Mirzaei H, Sahebkar A, Jaafari MR, Goodarzi M, Mirzaei HR (2017) Diagnostic and therapeutic potential of exosomes in cancer: the beginning of a new tale? J Cell Physiol 232:3251–3260

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Anschutz Medical Campus, Department of Neurosurgery, University of Colorado Denver, RC2, 12700 E 19th Ave, Room 5125, Aurora, CO, 80045, USA

    Michael W. Graner

  2. Department of Pediatrics, Division of Pediatric Hematology and Oncology, Masonic Cancer Center, University of Minnesota, MMC 806, 420 Delaware St SE, Minneapolis, MN, 55455, USA

    Sathya Schnell & Michael R. Olin

Authors
  1. Michael W. Graner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sathya Schnell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael R. Olin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael W. Graner.

Additional information

This article is a contribution to the special issue on Extracellular Vesicles - Guest Editor: Esther Nolte-'t Hoen

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Graner, M.W., Schnell, S. & Olin, M.R. Tumor-derived exosomes, microRNAs, and cancer immune suppression. Semin Immunopathol 40, 505–515 (2018). https://doi.org/10.1007/s00281-018-0689-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-018-0689-6

Keywords

Search

Navigation