The exosomes in tumor immunity

OncoImmunology

Volumn 4, Issue 9, 2015, Pages 1-8

  Liu, Yanfang ^a   Gu, Yan ^a   Cao, Xuetao ^a  

^a SECOND MILITARY MEDICAL UNIVERSITY   (China)

Author keywords

Exosomes; Extracellular vesicle; Immunosuppression; Intercellular communication; Tumor immunity; Tumor vaccine

Indexed keywords

GAMMA INTERFERON; HEAT SHOCK PROTEIN 72; INTERLEUKIN 16; INTERLEUKIN 6; INTERLEUKIN 8; JANUS KINASE 3; MICRORNA; MICRORNA 150; MICRORNA 378; MICRORNA 517C; MICRORNA 584; MONOCYTE CHEMOTACTIC PROTEIN 1; NATURAL CYTOTOXICITY TRIGGERING RECEPTOR 3; PROSTAGLANDIN E2; PROTEIN MCL 1; TISSUE INHIBITOR OF METALLOPROTEINASE 1; TOLL LIKE RECEPTOR 2; TRANSFORMING GROWTH FACTOR BETA ACTIVATED KINASE 1; TRANSFORMING GROWTH FACTOR BETA1; UNCLASSIFIED DRUG; WNT5A PROTEIN;

ANTIGEN PRESENTATION; ARTICLE; CANCER GROWTH; CANCER IMMUNOTHERAPY; CANCER INHIBITION; CD4+ CD25+ T LYMPHOCYTE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL MATURATION; CYTOTOXICITY; DENDRITIC CELL; DENDRITIC CELL DERIVED EXOSOME; DOWN REGULATION; EXOSOME; HUMAN; IMMUNE RESPONSE; IMMUNOSUPPRESSIVE TREATMENT; NATURAL KILLER T CELL; NONHUMAN; REGULATORY T LYMPHOCYTE; TUMOR DIFFERENTIATION; TUMOR IMMUNITY; TUMOR INVASION;

EID: 84944457654     PISSN: 21624011     EISSN: 2162402X     Source Type: Journal    
DOI: 10.1080/2162402X.2015.1027472     Document Type: Article

References (93)

1. Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 2009; 9:581-93; PMID:19498381; http://dx.doi.org/ 10.1038/nri2567
2. Gould SJ, Raposo G. As we wait: coping with an imperfect nomenclature for extracellular vesicles. J Extracell Vesicles 2013; 2:20389; PMID:24009890; http://dx.doi.org/10.3402/jev.v2i0.20389
3. Hegmans JP, Bard MP, Hemmes A, Luider TM, Kleijmeer MJ, Prins JB, Zitvogel L, Burgers SA, Hoogsteden HC, Lambrecht BN. Proteomic analysis of exosomes secreted by human mesothelioma cells. Am J Pathol 2004; 164:1807-15; PMID:15111327; http://dx.doi. org/10.1016/S0002-9440(10)63739-X
4. Webber J, Steadman R, Mason MD, Tabi Z, Clayton A. Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res 2010; 70:9621-30; PMID:21098712; http://dx.doi.org/10.1158/0008-5472.CAN-10-1722
5. XinH, Li Y, Buller B, KatakowskiM, Zhang Y,Wang X, Shang X, Zhang ZG, Chopp M. Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells 2012; 30:1556-64; PMID:22605481; http://dx.doi. org/10.1002/stem.1129
6. Colombo M, Raposo G, Thery C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol 2014; 30:255-89; PMID:25288114; http://dx.doi.org/ 10.1146/annurev-cellbio-101512-122326
7. Vlassov AV, Magdaleno S, Setterquist R, Conrad R. Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta 2012; 1820:940-8; PMID:22503788; http://dx.doi.org/10.1016/j.bbagen. 2012.03.017
8. Kim SH, Bianco NR, Shufesky WJ, Morelli AE, Robbins PD. MHC class IIC exosomes in plasma suppress inflammation in an antigen-specific and Fas ligand/Fasdependent manner. J Immunol 2007; 179:2235-41; PMID:17675484; http://dx.doi.org/10.4049/ jimmunol.179.4.2235
9. Dai S, Wei D,Wu Z, Zhou X, Wei X, Huang H, Li G. Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol Ther 2008; 16:782-90; PMID:18362931; http:// dx.doi.org/10.1038/mt.2008.1
10. Andre F, Schartz NE, Movassagh M, Flament C, Pautier P, Morice P, Pomel C, Lhomme C, Escudier B, Le Chevalier T et al. Malignant effusions and immunogenic tumour-derived exosomes. Lancet 2002; 360:295-305; PMID:12147373; http://dx.doi.org/ 10.1016/S0140-6736(02)09552-1
11. Kahlert C, Kalluri R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med (Berl) 2013; 91:431-7; PMID:23519402; http://dx.doi.org/10.1007/s00109-013-1020-6
12. Robbins PD, Morelli AE. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol 2014; 14:195-208; PMID:24566916; http://dx.doi. org/10.1038/nri3622
13. Melo SA, Sugimoto H, O'Connell JT, Kato N, Villanueva A, Vidal A, Qiu L, Vitkin E, Perelman LT, Melo CA et al. Cancer Exosomes Perform Cell-Independent MicroRNA Biogenesis and Promote Tumorigenesis. Cancer Cell 2014; 26:707-21; PMID:25446899; http://dx.doi.org/10.1016/j.ccell.2014.09.005
14. Taylor DD, Gercel-Taylor C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 2008; 110:13-21; PMID:18589210; http://dx.doi.org/10.1016/j.ygyno. 2008.04.033
15. Al-Nedawi K, Meehan B, Kerbel RS, Allison AC, Rak J. Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR. Proc Natl Acad Sci U S A 2009; 106:3794-9; PMID:19234131; http://dx.doi.org/ 10.1073/pnas.0804543106
16. Atay S, Banskota S, Crow J, Sethi G, Rink L, Godwin AK. Oncogenic KIT-containing exosomes increase gastrointestinal stromal tumor cell invasion. Proc Natl Acad Sci U S A 2014; 111:711-6; PMID:24379393; http://dx.doi.org/10.1073/pnas.1310501111
17. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007; 9:654-9; PMID:17486113; http://dx.doi.org/10.1038/ncb1596
18. Kogure T, Lin WL, Yan IK, Braconi C, Patel T. Intercellular nanovesicle-mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth. Hepatology 2011; 54:1237-48; PMID:21721029; http://dx.doi.org/10.1002/ hep.24504
19. Zhang Y, Liu D, Chen X, Li J, Li L, Bian Z, Sun F, Lu J, Yin Y, Cai X et al. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol Cell 2010; 39:133-44; PMID:20603081; http://dx.doi.org/ 10.1016/j.molcel.2010.06.010
20. Ohshima K, Inoue K, Fujiwara A, Hatakeyama K, Kanto K, Watanabe Y, Muramatsu K, Fukuda Y, Ogura S, Yamaguchi K et al. Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line. PLoS One 2010; 5:e13247; PMID:20949044; http:// dx.doi.org/10.1371/journal.pone.0013247
21. Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, Rak J. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 2008; 10:619-24; PMID:18425114; http://dx.doi.org/10.1038/ncb1725
22. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, García-Santos G, Ghajar C et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 2012; 18:883-91; PMID:22635005; http://dx. doi.org/10.1038/nm.2753
23. Xu H, Cao X. Dendritic cell vaccines in cancer immunotherapy: from biology to translational medicine. Front Med 2011; 5:323-32; PMID:22198743; http:// dx.doi.org/10.1007/s11684-011-0172-4
24. Condamine T, Gabrilovich DI. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol 2011; 32:19-25; PMID:21067974; http://dx.doi.org/10.1016/j. it.2010.10.002
25. Liu Y, Xiang X, Zhuang X, Zhang S, Liu C, Cheng Z, Michalek S, Grizzle W, Zhang HG. Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells. Am J Pathol 2010; 176:2490-9; PMID:20348242; http://dx.doi.org/ 10.2353/ajpath.2010.090777
26. Valenti R, Huber V, Filipazzi P, Pilla L, Sovena G, Villa A, Corbelli A, Fais S, Parmiani G, Rivoltini L. Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. Cancer Res 2006; 66:9290-8; PMID:16982774; http://dx.doi.org/10.1158/0008-5472.CAN-06-1819
27. Yu S, Liu C, Su K, Wang J, Liu Y, Zhang L, Li C, Cong Y, Kimberly R, Grizzle WE et al. Tumor exosomes inhibit differentiation of bone marrow dendritic cells. J Immunol 2007; 178:6867-75; PMID:17513735; http://dx.doi.org/ 10.4049/jimmunol.178.11.6867
28. Xiang X, Poliakov A, Liu C, Liu Y, Deng ZB, Wang J, Cheng Z, Shah SV, Wang GJ, Zhang L et al. Induction of myeloid-derived suppressor cells by tumor exosomes. Int J Cancer 2009; 124:2621-33; PMID:19235923; http://dx.doi.org/10.1002/ijc.24249
29. Chalmin F, Ladoire S, Mignot G, Vincent J, Bruchard M, Remy-Martin JP, Boireau W, Rouleau A, Simon B, Lanneau D et al. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest 2010; 120:457-71; PMID:20093776; http://dx.doi.org/ 10.1172/JCI40483
30. Yang C, Kim SH, Bianco NR, Robbins PD. Tumorderived exosomes confer antigen-specific immunosuppression in a murine delayed-type hypersensitivity model. PLoS One 2011; 6:e22517; PMID:21829629; http://dx.doi.org/10.1371/journal.pone.0022517
31. Zhou M, Chen J, Zhou L, Chen W, Ding G, Cao L. Pancreatic cancer derived exosomes regulate the expression of TLR4 in dendritic cells via miR-203. Cell Immunol 2014; 292:65-9; PMID:25290620; http:// dx.doi.org/10.1016/j.cellimm.2014.09.004
32. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature 2013; 496:445-55; PMID:23619691; http://dx.doi.org/ 10.1038/nature12034
33. Marton A, Vizler C, Kusz E, Temesfoi V, Szathmary Z, Nagy K, Szegletes Z, Varo G, Siklos L, Katona RL et al. Melanoma cell-derived exosomes alter macrophage and dendritic cell functions in vitro. Immunol Lett 2012; 148:34-8; PMID:22898052; http://dx.doi. org/10.1016/j.imlet.2012.07.006
34. Menck K, Klemm F, Gross JC, Pukrop T, Wenzel D, Binder C. Induction and transport of Wnt 5a during macrophage-induced malignant invasion is mediated by two types of extracellular vesicles. Oncotarget 2013; 4:2057-66; PMID:24185202
35. Xiang X, Liu Y, Zhuang X, Zhang S, Michalek S, Taylor DD, Grizzle W, Zhang HG. TLR2-mediated expansion ofMDSCs is dependent on the source of tumor exosomes. Am J Pathol 2010; 177:1606-10; PMID:20802178; http://dx.doi.org/10.2353/ajpath.2010.100245
36. Chow A, Zhou W, Liu L, Fong MY, Champer J, Van Haute D, Chin AR, Ren X, Gugiu BG, Meng Z et al. Macrophage immunomodulation by breast cancerderived exosomes requires Toll-like receptor 2-mediated activation of NF-kappaB. Sci Rep 2014; 4:5750; PMID:25034888; http://dx.doi.org/10.1038/srep05750
37. Boelens MC, Wu TJ, Nabet BY, Xu B, Qiu Y, Yoon T, Azzam DJ, Twyman-Saint Victor C, Wiemann BZ, Ishwaran H et al. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 2014; 159:499-513; PMID:25417103; http://dx. doi.org/10.1016/j.cell.2014.09.051
38. Vivier E, Ugolini S, Blaise D, Chabannon C, Brossay L. Targeting natural killer cells and natural killer T cells in cancer. Nat Rev Immunol 2012; 12:239-52; PMID:22437937; http://dx.doi.org/10.1038/nri3174
39. Lv LH, Wan YL, Lin Y, Zhang W, Yang M, Li GL, Lin HM, Shang CZ, Chen YJ, Min J. Anticancer drugs cause release of exosomes with heat shock proteins from human hepatocellular carcinoma cells that elicit effective natural killer cell antitumor responses in vitro. J Biol Chem 2012; 287:15874-85; PMID:22396543; http://dx.doi.org/10.1074/jbc.M112.340588
40. Groh V, Wu J, Yee C, Spies T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 2002; 419:734-8; PMID:12384702; http://dx.doi.org/10.1038/nature01112
41. Clayton A, Mitchell JP, Court J, Linnane S, Mason MD, Tabi Z. Human tumor-derived exosomes downmodulate NKG2D expression. J Immunol 2008; 180:7249-58; PMID:18490724; http://dx.doi.org/ 10.4049/jimmunol.180.11.7249
42. Szczepanski MJ, Szajnik M, Welsh A, Whiteside TL, Boyiadzis M. Blast-derived microvesicles in sera from patients with acute myeloid leukemia suppress natural killer cell function via membrane-associated transforming growth factor-beta1. Haematologica 2011; 96:1302-9; PMID:21606166; http://dx.doi.org/ 10.3324/haematol.2010.039743
43. Hedlund M, Nagaeva O, Kargl D, Baranov V, Mincheva-Nilsson L. Thermal-and oxidative stress causes enhanced release of NKG2D ligand-bearing immunosuppressive exosomes in leukemia/lymphoma T and B cells. PLoS One 2011; 6:e16899; PMID:21364924; http://dx.doi.org/10.1371/journal.pone.0016899
44. Klibi J, Niki T, Riedel A, Pioche-Durieu C, Souquere S, Rubinstein E, Le Moulec S, Guigay J, Hirashima M, Guemira F et al. Blood diffusion and Th1-suppressive effects of galectin-9-containing exosomes released by Epstein-Barr virus-infected nasopharyngeal carcinoma cells. Blood 2009; 113:1957-66; PMID:19005181; http://dx.doi.org/10.1182/blood-2008-02-142596
45. Liu ZM, Wang YB, Yuan XH. Exosomes from murinederived GL26 cells promote glioblastoma tumor growth by reducing number and function of CD8+T cells.Asian Pac J Cancer Prev 2013; 14:309-14; PMID:23534743; http://dx.doi.org/10.7314/APJCP.2013.14.1.309
46. Kim HR, Jeon BH, Lee HS, Im SH, Araki M, Araki K, Yamamura K, Choi SC, Park DS, Jun CD. IGSF4 is a novel TCR zeta-chain-interacting protein that enhances TCR-mediated signaling. J Exp Med 2011; 208:2545-60; PMID:22084409; http://dx.doi.org/10.1084/ jem.20110853
47. Soderberg A, Barral AM, Soderstrom M, Sander B, Rosen A. Redox-signaling transmitted in trans to neighboring cells by melanoma-derived TNF-containing exosomes. Free Radic Biol Med 2007; 43:90-9; PMID:17561097; http://dx.doi.org/10.1016/j.freeradbiomed.2007.03.026
48. Abusamra AJ, Zhong Z, Zheng X, Li M, Ichim TE, Chin JL, Min WP. Tumor exosomes expressing Fas ligand mediate CD8+ T-cell apoptosis. Blood Cells Mol Dis 2005; 35:169-73; PMID:16081306; http:// dx.doi.org/10.1016/j.bcmd.2005.07.001
49. Wieckowski EU, Visus C, Szajnik M, Szczepanski MJ, Storkus WJ, Whiteside TL. Tumor-derived microvesicles promote regulatory T cell expansion and induce apoptosis in tumor-reactive activated CD8+ T lymphocytes. J Immunol 2009; 183:3720-30; PMID:19692638; http:// dx.doi.org/10.4049/jimmunol.0900970
50. Andreola G, Rivoltini L, Castelli C, Huber V, Perego P, Deho P, Squarcina P, Accornero P, Lozupone F, Lugini L et al. Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. J Exp Med 2002; 195:1303-16; PMID:12021310; http://dx.doi.org/10.1084/jem.20011624
51. Taylor DD, Gercel-Taylor C. Tumour-derived exosomes and their role in cancer-associatedT-cell signalling defects. Br J Cancer 2005; 92:305-11;PMID:15655551
52. CaiZ, ZhangW,Yang F,Yu L,YuZ, PanJ,Wang L, Cao X, Wang J. Immunosuppressive exosomes from TGFbeta1 gene-modified dendritic cells attenuate Th17-mediated inflammatory autoimmune disease by inducing regulatory T cells. Cell Res 2012; 22:607-10; PMID:22157651; http://dx.doi.org/10.1038/cr.2011.196
53. Yu L, Yang F, Jiang L, Chen Y, Wang K, Xu F, Wei Y, Cao X,Wang J, Cai Z. Exosomes with membrane-associated TGF-βeta1 from gene-modified dendritic cells inhibit murine EAE independently of MHC restriction. Eur J Immunol 2013; 43:2461-72; PMID:23716181; http://dx.doi.org/10.1002/eji.201243295
54. Cai Z, Yang F, Yu L, Yu Z, Jiang L, Wang Q, Yang Y, Wang L, Cao X, Wang J. Activated T cell exosomes promote tumor invasion via Fas signaling pathway. J Immunol 2012; 188:5954-61; PMID:22573809; http://dx.doi.org/10.4049/jimmunol.1103466
55. Han Y, Guo Q, Zhang M, Chen Z, Cao X. CD69+ CD4+ CD25-T cells, a new subset of regulatory T cells, suppress T cell proliferation through membranebound TGF-βeta 1. J Immunol 2009; 182:111-20; PMID:19109141; http://dx.doi.org/10.4049/ jimmunol.182.1.111
56. Szajnik M, Czystowska M, Szczepanski MJ, Mandapathil M, Whiteside TL. Tumor-derived microvesicles induce, expand and up-regulate biological activities of human regulatory T cells (Treg). PLoS One 2010; 5: e11469; PMID:20661468; http://dx.doi.org/10.1371/ journal.pone.0011469
57. Yin Y, Cai X, Chen X, Liang H, Zhang Y, Li J, Wang Z, Chen X, Zhang W, Yokoyama S et al. Tumorsecreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth. Cell Res 2014; 24:1164-80; PMID:25223704; http://dx. doi.org/10.1038/cr.2014.121
58. Okoye IS, Coomes SM, Pelly VS, Czieso S, Papayannopoulos V, Tolmachova T, Seabra MC, Wilson MS. MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells. Immunity 2014; 41:89-103; PMID:25035954; http://dx.doi.org/ 10.1016/j.immuni.2014.05.019
59. Xie Y, Zhang X, Zhao T, Li W, Xiang J. Natural CD8 (+)25(+) regulatory T cell-secreted exosomes capable of suppressing cytotoxic T lymphocyte-mediated immunity against B16 melanoma. Biochem Biophys Res Commun 2013; 438:152-5; PMID:23876314; http://dx.doi.org/10.1016/j.bbrc.2013.07.044
60. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, Geuze HJ. B lymphocytes secrete antigen-presenting vesicles. J Exp Med 1996; 183:1161-72; PMID:8642258; http://dx.doi.org/ 10.1084/jem.183.3.1161
61. Yang C, Chalasani G, Ng YH, Robbins PD. Exosomes released from Mycoplasma infected tumor cells activate inhibitory B cells. PLoS One 2012; 7:e36138; PMID:22558358; http://dx.doi.org/10.1371/journal. pone.0036138
62. Galluzzi L, Senovilla L, Vacchelli E, Eggermont A, Fridman WH, Galon J, Sautès-Fridman C, Tartour E, Zitvogel L, Kroemer G. Trial watch: Dendritic cellbased interventions for cancer therapy. Oncoimmunology 2012; 1:1111-34; PMID:23170259; http://dx.doi. org/10.4161/onci.21494
63. Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, Ricciardi-Castagnoli P, Raposo G, Amigorena S. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med 1998; 4:594-600; PMID:9585234; http://dx.doi. org/10.1038/nm0598-594
64. Thery C, Boussac M, Veron P, Ricciardi-Castagnoli P, Raposo G, Garin J, Amigorena S. Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J Immunol 2001; 166:7309-18; PMID:11390481; http://dx. doi.org/10.4049/jimmunol.166.12.7309
65. Clayton A, Court J, Navabi H, Adams M, Mason MD, Hobot JA, Newman GR, Jasani B. Analysis of antigen presenting cell derived exosomes, based on immunomagnetic isolation and flow cytometry. J Immunol Methods 2001; 247:163-74; PMID:11150547; http:// dx.doi.org/10.1016/S0022-1759(00)00321-5
66. Andre F, Chaput N, Schartz NE, Flament C, Aubert N, Bernard J, Lemonnier F, Raposo G, Escudier B, Hsu DH et al. 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 2004; 172:2126-36; PMID:14764678; http:// dx.doi.org/10.4049/jimmunol.172.4.2126
67. Segura E, Nicco C, Lombard B, Veron P, Raposo G, Batteux F, Amigorena S, Théry C. ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming. Blood 2005; 106:216-23; PMID:15790784; http://dx.doi.org/10.1182/blood-2005-01-0220
68. Thery C, Regnault A, Garin J,Wolfers J, Zitvogel L, Ricciardi-Castagnoli P, Raposo G, Amigorena S. Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. J Cell Biol 1999; 147:599-610; PMID:10545503; http://dx. doi.org/10.1083/jcb.147.3.599
69. Pitt JM, Charrier M, Viaud S, Andre F, Besse B, Chaput N, Zitvogel L. Dendritic cell-derived exosomes as immunotherapies in the fight against cancer. J Immunol 2014; 193:1006-11; PMID:25049431; http://dx. doi.org/10.4049/jimmunol.1400703
70. Hao S, Bai O, Yuan J, Qureshi M, Xiang J. Dendritic cell-derived exosomes stimulate stronger CD8+ CTL responses and antitumor immunity than tumor cellderived exosomes. Cell Mol Immunol 2006; 3:205-11; PMID:16893501
71. Naslund TI, Gehrmann U, Qazi KR, Karlsson MC, Gabrielsson S. Dendritic cell-derived exosomes need to activate both T and B cells to induce antitumor immunity. J Immunol 2013; 190:2712-9; PMID:23418627; http://dx.doi.org/10.4049/jimmunol.1203082
72. Vincent-Schneider H, Stumptner-Cuvelette P, Lankar D, Pain S, Raposo G, Benaroch P, Bonnerot C. Exosomes bearing HLA-DR1 molecules need dendritic cells to efficiently stimulate specific T cells. Int Immunol 2002; 14:713-22; PMID:12096030; http://dx.doi. org/10.1093/intimm/dxf048
73. Thery C, Duban L, Segura E, Veron P, Lantz O, Amigorena S. Indirect activation of naive CD4+ T cells by dendritic cell-derived exosomes. Nat Immunol 2002; 3:1156-62; PMID:12426563; http://dx.doi.org/ 10.1038/ni854
74. Munich S, Sobo-Vujanovic A, BuchserWJ, Beer-Stolz D, VujanovicNL. Dendritic cell exosomes directly kill tumor cells and activate natural killer cells via TNF superfamily ligands. Oncoimmunology 2012; 1:1074-83; PMID:23170255; http://dx.doi.org/10.4161/onci.20897
75. Viaud S, Terme M, Flament C, Taieb J, Andre F, Novault S, Escudier B, Robert C, Caillat-Zucman S, Tursz T et al. Dendritic cell-derived exosomes promote natural killer cell activation and proliferation: a role for NKG2D ligands and IL-15Ralpha. PLoS One 2009; 4: e4942; PMID:19319200; http://dx.doi.org/10.1371/ journal.pone.0004942
76. Simhadri VR, Reiners KS, Hansen HP, Topolar D, Simhadri VL, Nohroudi K, Kufer TA, Engert A, Pogge von Strandmann E. Dendritic cells release HLA-B-associated transcript-3 positive exosomes to regulate natural killer function. PLoS One 2008; 3:e3377; PMID:18852879; http://dx.doi.org/10.1371/journal. pone.0003377
77. Escudier B, Dorval T, Chaput N, Andre F, Caby MP, Novault S, Flament C, Leboulaire C, Borg C, Amigorena S et al. Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derivedexosomes: results of thefirst phase I clinical trial. J Transl Med 2005; 3:10; PMID:15740633; http://dx. doi.org/10.1186/1479-5876-3-10
78. Morse MA, Garst J, Osada T, Khan S, Hobeika A, Clay TM, Valente N, Shreeniwas R, Sutton MA, Delcayre A et al. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J Transl Med 2005; 3:9; PMID:15723705; http://dx. doi.org/10.1186/1479-5876-3-9
79. Wolfers J, Lozier A, Raposo G, Regnault A, Thery C, Masurier C, Flament C, Pouzieux S, Faure F, Tursz T et al. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med 2001; 7:297-303; PMID:11231627; http://dx. doi.org/10.1038/85438
80. Altieri SL, Khan AN, Tomasi TB. Exosomes from plasmacytoma cells as a tumor vaccine. J Immunother 2004; 27:282-8; PMID:15235389; http://dx.doi.org/ 10.1097/00002371-200407000-00004
81. Li W, Mu D, Tian F, Hu Y, Jiang T, Han Y, Chen J, Han G, Li X. Exosomes derived from Rab27aoverexpressing tumor cells elicit efficient induction of antitumor immunity. Mol Med Rep 2013; 8:1876-82; PMID:24146068; http://dx.doi.org/ 10.3892/mmr.2013.1738
82. Yang Y, Xiu F, Cai Z, Wang J, Wang Q, Fu Y, Cao X. Increased induction of antitumor response by exosomes derived from interleukin-2 gene-modified tumor cells. J Cancer Res Clin Oncol 2007; 133:389-99; PMID:17219198; http://dx.doi.org/10.1007/s00432-006-0184-7
83. Dai S, Zhou X, Wang B, Wang Q, Fu Y, Chen T,Wan T, Yu Y, Cao X. Enhanced induction of dendritic cell maturation and HLA-A *0201-restricted CEA-specific CD8(+) CTL response by exosomes derived from IL-18 gene-modified CEA-positive tumor cells. J Mol Med (Berl) 2006; 84:1067-76; PMID:17016692; http://dx.doi.org/10.1007/s00109-006-0102-0
84. Yao Y, Chen L, Wei W, Deng X, Ma L, Hao S. Tumor cell-derived exosome-targeted dendritic cells stimulate stronger CD8+ CTL responses and antitumor immunities. Biochem Biophys Res Commun 2013; 436:60-5; PMID:23707941; http://dx.doi.org/10.1016/j. bbrc.2013.05.058
85. Wang J, Wang L, Lin Z, Tao L, Chen M. More efficient induction of antitumor T cell immunity by exosomes from CD40L gene-modified lung tumor cells. Mol Med Rep 2014; 9:125-31; PMID:24173626; http://dx.doi.org/10.3892/mmr.2013.1759
86. Fan W, Tian XD, Huang E, Zhang JJ. Exosomes from CIITA-transfected CT26 cells enhance anti-tumor effects. Asian Pac J Cancer Prev 2013; 14:987-91; PMID:23621273; http://dx.doi.org/10.7314/APJCP. 2013.14.2.987
87. Xie Y, Bai O, Zhang H, Li W, Xiang J. Tumor necrosis factor gene-engineered J558 tumor cell-released exosomes stimulate tumor antigen P1A-specific CD8+ CTL responses and antitumor immunity. Cancer Biother Radiopharm 2010; 25:21-8; PMID:20187793; http://dx.doi.org/10.1089/cbr.2009.0714
88. Chen W, Wang J, Shao C, Liu S, Yu Y,Wang Q, Cao X. Efficient induction of antitumor T cell immunity by exosomes derived from heat-shocked lymphoma cells. Eur J Immunol 2006; 36:1598-607; PMID:16708399; http:// dx.doi.org/10.1002/eji.200535501
89. Dai S, Wan T, Wang B, Zhou X, Xiu F, Chen T, Wu Y, Cao X. More efficient induction of HLA-A *0201-restricted and carcinoembryonic antigen (CEA)-specific CTL response by immunization with exosomes prepared from heat-stressed CEA-positive tumor cells. Clin Cancer Res 2005; 11:7554-63; PMID:16243831; http://dx.doi.org/10.1158/1078-0432.CCR-05-0810
90. Chen T, Guo J, Yang M, Zhu X, Cao X. Chemokinecontaining exosomes are released from heat-stressed tumor cells via lipid raft-dependent pathway and act as efficient tumor vaccine. J Immunol 2011; 186:2219-28; PMID:21242526; http://dx.doi.org/10.4049/ jimmunol.1002991
91. Xiu F, Cai Z, Yang Y,Wang X, Wang J, Cao X. Surface anchorage of superantigen SEA promotes induction of specific antitumor immune response by tumor-derived exosomes. J Mol Med (Berl) 2007; 85:511-21; PMID:17219095; http://dx.doi.org/10.1007/s00109-006-0154-1
92. Guo F, Chang CK, Fan HH, Nie XX, Ren YN, Liu YY, Zhao LH. Anti-tumour effects of exosomes in combination with cyclophosphamide and polyinosinic-polycytidylic acid. J Int Med Res 2008; 36:1342-53; PMID:19094445; http://dx.doi.org/10.1177/ 147323000803600623
93. RenWN, Chang CK, Fan HH,Guo F, Ren YN, Yang J, Guo J, Li X. A combination of exosomes carrying TSA derived from HLA-A2-positive human white buffy coat and polyI:C for use as a subcellular antitumor vaccination. J Immunoassay Immunochem 2011; 32:207-18; PMID:21574092; http://dx.doi.org/10.1080/ 15321819.2011.559295