Exosome and Secretion: Action On?

  • Ye HuEmail author
  • Rui Zhang
  • Gang Chen
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1248)


Originally treated as part of a cellular waste, extracellular vesicles (EVs) are being shown to possess a vast variety of functions, of which exosome is the most studied one. Most cells, such as tumor cells, immunocytes, and fibroblasts can secrete exosomes, especially under certain stresses the amount is much higher, and the contents of exosome represent the status of the donor cells and the tumor microenvironment. As crucial transporters for cells’ content exchange, much attention has been raised in the utilities of exosomes to suppress immune response, and to modify a microenvironment favorable for cancer progression. Exosomal immune checkpoints, such as programmed cell death ligand 1 (PD-L1), contribute to immunosuppression and are associated with anti-PD-1 response. Many forms of soluble immune checkpoint receptors have also been shown to influence efficacy mediated by their therapeutic antibodies. Therefore, targeting pro-tumorous exosomes may achieve antitumor effect supplementary to existing therapies. Exosome, itself natural liposome-like structure, allows it to be a potential drug delivery tool.


Tumor-derived exosome Exosomal PD-L1 Soluble immune checkpoint receptors miRNA 


  1. Alguacil-Nunez C, Ferrer-Ortiz I, Garcia-Verdu E, Lopez-Pirez P, Llorente-Cortijo IM, Sainz B Jr (2018) Current perspectives on the crosstalk between lung cancer stem cells and cancer-associated fibroblasts. Crit Rev Oncology/Hematology 125:102–110CrossRefGoogle Scholar
  2. Alvarez ML, Khosroheidari M, Kanchi Ravi R, DiStefano JK (2012) Comparison of protein, microrna, and mrna yields using different methods of urinary exosome isolation for the discovery of kidney disease biomarkers. Kidney Int 82:1024–1032CrossRefGoogle Scholar
  3. Amzallag N, Passer BJ, Allanic D, Segura E, Thery C, Goud B, Amson R, Telerman A (2004) Tsap6 facilitates the secretion of translationally controlled tumor protein/histamine-releasing factor via a nonclassical pathway. J Biol Chem 279:46104–46112CrossRefGoogle Scholar
  4. Andre F, Schartz NE, Movassagh M, Flament C, Pautier P, Morice P, Pomel C, Lhomme C, Escudier B, Le Chevalier T, Tursz T, Amigorena S, Raposo G, Angevin E, Zitvogel L (2002) Malignant effusions and immunogenic tumour-derived exosomes. Lancet 360:295–305CrossRefGoogle Scholar
  5. Ashiru O, Boutet P, Fernandez-Messina L, Aguera-Gonzalez S, Skepper JN, Vales-Gomez M, Reyburn HT (2010) Natural killer cell cytotoxicity is suppressed by exposure to the human NKG2D ligand MICA*008 that is shed by tumor cells in exosomes. Can Res 70:481–489CrossRefGoogle Scholar
  6. Azoulay-Alfaguter I, Mor A (2018) Proteomic analysis of human T cell-derived exosomes reveals differential RAS/MAPK signaling. Eur J Immunol 48:1915–1917CrossRefPubMedPubMedCentralGoogle Scholar
  7. Batista BS, Eng WS, Pilobello KT, Hendricks-Munoz KD, Mahal LK (2011) Identification of a conserved glycan signature for microvesicles. J Proteome Res 10:4624–4633CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T (1999) Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285:727–729CrossRefGoogle Scholar
  9. 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-β and miR23a transfer. Oncoimmunology. 5:e1062968CrossRefGoogle Scholar
  10. Bhome R, Goh RW, Bullock MD, Pillar N, Thirdborough SM, Mellone M, Mirnezami R, Galea D, Veselkov K, Gu Q, Underwood TJ, Primrose JN, De Wever O, Shomron N, Sayan AE, Mirnezami AH (2017) Exosomal microRNAs derived from colorectal cancer-associated fibroblasts: role in driving cancer progression. Aging 9:2666–2694CrossRefPubMedPubMedCentralGoogle Scholar
  11. Borrelli C, Ricci B, Vulpis E, Fionda C, Ricciardi MR, Petrucci MT, Masuelli L, Peri A, Cippitelli M, Zingoni A, Santoni A, Soriani A (2018) Drug-induced senescent multiple myeloma cells elicit nk cell proliferation by direct or exosome-mediated il15 trans-presentation. Cancer Immunol Res 6:860–869CrossRefGoogle Scholar
  12. Burke M, Choksawangkarn W, Edwards N, Ostrand-Rosenberg S, Fenselau C (2014) Exosomes from myeloid-derived suppressor cells carry biologically active proteins. J Proteome Res 13:836–843CrossRefGoogle Scholar
  13. Cervantes JL, Weinerman B, Basole C, Salazar JC (2012) TLR8: The forgotten relative revindicated. Cell Mol Immunol 9:434–438CrossRefPubMedPubMedCentralGoogle Scholar
  14. Cha DJ, Franklin JL, Dou Y, Liu Q, Higginbotham JN, Demory Beckler M, Weaver AM, Vickers K, Prasad N, Levy S, Zhang B, Coffey RJ, Patton JG (2015) KRAS-dependent sorting of mirna to exosomes. eLife 4:e07197Google Scholar
  15. 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 107Google Scholar
  16. Chen L, Han X (2015) Anti-PD-1/PD-l1 therapy of human cancer: past, present, and future. J Clin Investig 125:3384–3391CrossRefGoogle Scholar
  17. Chen DS, Mellman I (2017) Elements of cancer immunity and the cancer–immune set point. Nature 541:321–330CrossRefPubMedPubMedCentralGoogle Scholar
  18. Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, Yu Z, Yang J, Wang B, Sun H, Xia H, Man Q, Zhong W, Antelo LF, Wu B, Xiong X, Liu X, Guan L, Li T, Liu S, Yang R, Lu Y, Dong L, McGettigan S, Somasundaram R, Radhakrishnan R, Mills G, Lu Y, Kim J, Chen YH, Dong H, Zhao Y, Karakousis GC, Mitchell TC, Schuchter LM, Herlyn M, Wherry EJ, Xu X, Guo W (2018a) Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560:382–386CrossRefPubMedPubMedCentralGoogle Scholar
  19. Chen S, Lv M, Fang S, Ye W, Gao Y, Xu Y (2018b) Poly (I:C) enhanced anti-cervical cancer immunities induced by dendritic cells-derived exosomes. Int J Biol Macromol 113:1182–1187CrossRefGoogle Scholar
  20. Cheng WC, Liao TT, Lin CC, Yuan LE, Lan HY, Lin HH, Teng HW, Chang HC, Lin CH, Yang CY, Huang SC, Jiang JK, Yang SH, Yang MH, Hwang WL (2019) RAB27b-activated secretion of stem-like tumor exosomes delivers the biomarker microRNA-146a-5p, which promotes tumorigenesis and associates with an immunosuppressive tumor microenvironment in colorectal cancer. Int J Cancer 145:2209–2224CrossRefGoogle Scholar
  21. Chiodoni C, Di Martino MT, Zazzeroni F, Caraglia M, Donadelli M, Meschini S, Leonetti C, Scotlandi K (2019) Cell communication and signaling: how to turn bad language into positive one. J Exper Clin Cancer Res CR 38:128CrossRefGoogle Scholar
  22. Chow A, Zhou W, Liu L, Fong MY, Champer J, Van Haute D, Chin AR, Ren X, Gugiu BG, Meng Z, Huang W, Ngo V, Kortylewski M, Wang SE (2014) Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-κB. Sci Rep 4:5750CrossRefPubMedPubMedCentralGoogle Scholar
  23. Chulpanova DS, Kitaeva KV, James V, Rizvanov AA, Solovyeva VV (2018) Therapeutic prospects of extracellular vesicles in cancer treatment. Front Immunol 9:1534CrossRefPubMedPubMedCentralGoogle Scholar
  24. Clayton A, Mitchell JP, Court J, Linnane S, Mason MD, Tabi Z (2008) Human tumor-derived exosomes down-modulate NKG2D expression. J Immunol 180:7249–7258CrossRefGoogle Scholar
  25. 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 122:1411–1418CrossRefGoogle Scholar
  26. Colombo M, Raposo G, Thery C (2014) Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Ann Rev Cell Dev Biol 30:255–289CrossRefGoogle Scholar
  27. Conigliaro A, Costa V, Lo Dico A, Saieva L, Buccheri S, Dieli F, Manno M, Raccosta S, Mancone C, Tripodi M, De Leo G, Alessandro R (2015) CD90+ liver cancer cells modulate endothelial cell phenotype through the release of exosomes containing H19 lncRNA. Mol Cancer 14:155CrossRefPubMedPubMedCentralGoogle Scholar
  28. Consortium E-T, Van Deun J, Mestdagh P, Agostinis P, Akay O, Anand S, Anckaert J, Martinez ZA, Baetens T, Beghein E, Bertier L, Berx G, Boere J, Boukouris S, Bremer M, Buschmann D, Byrd JB, Casert C, Cheng L, Cmoch A, Daveloose D, De Smedt E, Demirsoy S, Depoorter V, Dhondt B, Driedonks TA, Dudek A, Elsharawy A, Floris I, Foers AD, Gartner K, Garg AD, Geeurickx E, Gettemans J, Ghazavi F, Giebel B, Kormelink TG, Hancock G, Helsmoortel H, Hill AF, Hyenne V, Kalra H, Kim D, Kowal J, Kraemer S, Leidinger P, Leonelli C, Liang Y, Lippens L, Liu S, Lo Cicero A, Martin S, Mathivanan S, Mathiyalagan P, Matusek T, Milani G, Monguio-Tortajada M, Mus LM, Muth DC, Nemeth A, Nolte-’t Hoen EN, O’Driscoll L, Palmulli R, Pfaffl MW, Primdal-Bengtson B, Romano E, Rousseau Q, Sahoo S, Sampaio N, Samuel M, Scicluna B, Soen B, Steels A, Swinnen JV, Takatalo M, Thaminy S, Thery C, Tulkens J, Van Audenhove I, van der Grein S, Van Goethem A, van Herwijnen MJ, Van Niel G, Van Roy N, Van Vliet AR, Vandamme N, Vanhauwaert S, Vergauwen G, Verweij F, Wallaert A, Wauben M, Witwer KW, Zonneveld MI, De Wever O, Vandesompele J, Hendrix A (2017) Ev-track: transparent reporting and centralizing knowledge in extracellular vesicle research. Nat Methods 14:228–232Google Scholar
  29. Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic ras and the p53 tumor suppressor. PLoS Biol 6:2853–2868CrossRefGoogle Scholar
  30. 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 J Am Soc Gene Ther 16:782–790CrossRefGoogle Scholar
  31. Diamond JM, Vanpouille-Box C, Spada S, Rudqvist NP, Chapman JR, Ueberheide BM, Pilones KA, Sarfraz Y, Formenti SC, Demaria S (2018) Exosomes shuttle TREX1-sensitive ifn-stimulatory dsdna from irradiated cancer cells to dcs. Cancer Immunol Res 6:910–920CrossRefPubMedPubMedCentralGoogle Scholar
  32. Dickens AM, Tovar YRLB, Yoo SW, Trout AL, Bae M, Kanmogne M, Megra B, Williams DW, Witwer KW, Gacias M, Tabatadze N, Cole RN, Casaccia P, Berman JW, Anthony DC, Haughey NJ (2017) Astrocyte-shed extracellular vesicles regulate the peripheral leukocyte response to inflammatory brain lesions. Sci Signal 10Google Scholar
  33. 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 6:29877–29888PubMedPubMedCentralGoogle Scholar
  34. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800CrossRefGoogle Scholar
  35. 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 USA 109:2110–2116CrossRefGoogle Scholar
  36. Fan Y, Herr F, Vernochet A, Mennesson B, Oberlin E, Durrbach A (2019) Human fetal liver mesenchymal stem cell-derived exosomes impair natural killer cell function. Stem Cells Dev 28:44–55CrossRefGoogle Scholar
  37. Fang JH, Zhang ZJ, Shang LR, Luo YW, Lin YF, Yuan Y, Zhuang SM (2018) Hepatoma cell-secreted exosomal microRNA-103 increases vascular permeability and promotes metastasis by targeting junction proteins. Hepatology 68:1459–1475CrossRefPubMedPubMedCentralGoogle Scholar
  38. Fernandez-Messina L, Ashiru O, Boutet P, Aguera-Gonzalez S, Skepper JN, Reyburn HT, Vales-Gomez M (2010) Differential mechanisms of shedding of the glycosylphosphatidylinositol (GPI)-anchored NKG2D ligands. J Biol Chem 285:8543–8551CrossRefPubMedPubMedCentralGoogle Scholar
  39. Frigola X, Inman BA, Lohse CM, Krco CJ, Cheville JC, Thompson RH, Leibovich B, Blute ML, Dong H, Kwon ED (2011) Identification of a soluble form of B7-H1 that retains immunosuppressive activity and is associated with aggressive renal cell carcinoma. Clin Cancer Res 17:1915–1923 An Official Journal of the American Association for Cancer ResearchCrossRefPubMedPubMedCentralGoogle Scholar
  40. Gao D, Jiang L (2018) Exosomes in cancer therapy: a novel experimental strategy. Am J Cancer Res 8:2165–2175PubMedPubMedCentralGoogle Scholar
  41. Geis-Asteggiante L, Belew AT, Clements VK, Edwards NJ, Ostrand-Rosenberg S, El-Sayed NM, Fenselau C (2018) Differential content of proteins, mRNAs, and miRNAs suggests that MDSC and their exosomes may mediate distinct immune suppressive functions. J Proteome Res 17:486–498CrossRefGoogle Scholar
  42. Goulet CR, Champagne A, Bernard G, Vandal D, Chabaud S, Pouliot F, Bolduc S (2019) Cancer-associated fibroblasts induce epithelial-mesenchymal transition of bladder cancer cells through paracrine IL-6 signalling. BMC Cancer 19:137CrossRefPubMedPubMedCentralGoogle Scholar
  43. 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 Official Publication of the Federation of American Societies for Experimental BiologyCrossRefPubMedPubMedCentralGoogle Scholar
  44. Graner MW, Schnell S, Olin MR (2018) Tumor-derived exosomes, micrornas, and cancer immune suppression. Semin Immunopathol 40:505–515CrossRefPubMedPubMedCentralGoogle Scholar
  45. Groh V, Wu J, Yee C, Spies T (2002) Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419:734–738CrossRefGoogle Scholar
  46. 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 384:267–279CrossRefGoogle Scholar
  47. 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 22:549–556PubMedGoogle Scholar
  48. Haderk F, Schulz R, Iskar M, Cid LL, Worst T, Willmund KV, Schulz A, Warnken U, Seiler J, Benner A, Nessling M, Zenz T, Gobel M, Durig J, Diederichs S, Paggetti J, Moussay E, Stilgenbauer S, Zapatka M, Lichter P, Seiffert M (2017) Tumor-derived exosomes modulate PD-L1 expression in monocytes. Sci Immunol 2Google Scholar
  49. Hagemann T, Biswas SK, Lawrence T, Sica A, Lewis CE (2009) Regulation of macrophage function in tumors: the multifaceted role of NF-κB. Blood 113:3139–3146CrossRefPubMedPubMedCentralGoogle Scholar
  50. Han L, Lam EW, Sun Y (2019) Extracellular vesicles in the tumor microenvironment: old stories, but new tales. Mol Cancer 18:59CrossRefPubMedPubMedCentralGoogle Scholar
  51. Harding C, Heuser J, Stahl P (1983) Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol 97:329–339CrossRefGoogle Scholar
  52. He L, Zhang G, He Y, Zhu H, Zhang H, Feng Z (2005) Blockade of B7-H1 with sPD-1 improves immunity against murine hepatocarcinoma. Anticancer Res 25:3309–3313PubMedGoogle Scholar
  53. 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:e16899CrossRefPubMedPubMedCentralGoogle Scholar
  54. Herrera M, Llorens C, Rodriguez M, Herrera A, Ramos R, Gil B, Candia A, Larriba MJ, Garre P, Earl J, Rodriguez-Garrote M, Caldes T, Bonilla F, Carrato A, Garcia-Barberan V, Pena C (2018) Differential distribution and enrichment of non-coding rnas in exosomes from normal and cancer-associated fibroblasts in colorectal cancer. Mol Cancer 17:114CrossRefPubMedPubMedCentralGoogle Scholar
  55. Hsieh CH, Tai SK, Yang MH (2018) Snail-overexpressing cancer cells promote M2-like polarization of tumor-associated macrophages by delivering MiR-21-abundant exosomes. Neoplasia 20:775–788CrossRefPubMedPubMedCentralGoogle Scholar
  56. Hui E, Cheung J, Zhu J, Su X, Taylor MJ, Wallweber HA, Sasmal DK, Huang J, Kim JM, Mellman I, Vale RD (2017) T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355:1428–1433CrossRefPubMedPubMedCentralGoogle Scholar
  57. 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 13:421CrossRefPubMedPubMedCentralGoogle Scholar
  58. Javidi-Sharifi N, Martinez J, English I, Joshi SK, Scopim-Ribeiro R, Viola SK, Edwards DKt, Agarwal A, Lopez C, Jorgens D, Tyner JW, Druker BJ, Traer E (2019) FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells. eLife 8Google Scholar
  59. Jong AY, Wu CH, Li J, Sun J, Fabbri M, Wayne AS, Seeger RC (2017) Large-scale isolation and cytotoxicity of extracellular vesicles derived from activated human natural killer cells. J Extracell Vesicles 6:1294368CrossRefPubMedPubMedCentralGoogle Scholar
  60. Kachapati K, Bednar KJ, Adams DE, Wu Y, Mittler RS, Jordan MB, Hinerman JM, Herr AB, Ridgway WM (2013) Recombinant soluble CD137 prevents type one diabetes in nonobese diabetic mice. J Autoimmun 47:94–103CrossRefGoogle Scholar
  61. Kim DK, Lee J, Kim SR, Choi DS, Yoon YJ, Kim JH, Go G, Nhung D, Hong K, Jang SC, Kim SH, Park KS, Kim OY, Park HT, Seo JH, Aikawa E, Baj-Krzyworzeka M, van Balkom BW, Belting M, Blanc L, Bond V, Bongiovanni A, Borras FE, Buee L, Buzas EI, Cheng L, Clayton A, Cocucci E, Dela Cruz CS, Desiderio DM, Di Vizio D, Ekstrom K, Falcon-Perez JM, Gardiner C, Giebel B, Greening DW, Gross JC, Gupta D, Hendrix A, Hill AF, Hill MM, Nolte-’t Hoen E, Hwang DW, Inal J, Jagannadham MV, Jayachandran M, Jee YK, Jorgensen M, Kim KP, Kim YK, Kislinger T, Lasser C, Lee DS, Lee H, van Leeuwen J, Lener T, Liu ML, Lotvall J, Marcilla A, Mathivanan S, Moller A, Morhayim J, Mullier F, Nazarenko I, Nieuwland R, Nunes DN, Pang K, Park J, Patel T, Pocsfalvi G, Del Portillo H, Putz U, Ramirez MI, Rodrigues ML, Roh TY, Royo F, Sahoo S, Schiffelers R, Sharma S, Siljander P, Simpson RJ, Soekmadji C, Stahl P, Stensballe A, Stepien E, Tahara H, Trummer A, Valadi H, Vella LJ, Wai SN, Witwer K, Yanez-Mo M, Youn H, Zeidler R, Gho YS (2015) Evpedia: a community web portal for extracellular vesicles research. Bioinformatics 31:933–939CrossRefGoogle Scholar
  62. Kitai Y, Kawasaki T, Sueyoshi T, Kobiyama K, Ishii KJ, Zou J, Akira S, Matsuda T, Kawai T (2017) DNA-containing exosomes derived from cancer cells treated with topotecan activate a sting-dependent pathway and reinforce antitumor immunity. J Immunol 198:1649–1659CrossRefGoogle Scholar
  63. Komatsu S, Ichikawa D, Takeshita H, Morimura R, Hirajima S, Tsujiura M, Kawaguchi T, Miyamae M, Nagata H, Konishi H, Shiozaki A, Otsuji E (2014) Circulating miR-18a: a sensitive cancer screening biomarker in human cancer. Vivo 28:293–297Google Scholar
  64. 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 285:17442–17452CrossRefPubMedPubMedCentralGoogle Scholar
  65. Kruger S, Legenstein ML, Rosgen V, Haas M, Modest DP, Westphalen CB, Ormanns S, Kirchner T, Heinemann V, Holdenrieder S, Boeck S (2017) Serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) in advanced pancreatic cancer. Oncoimmunology 6:e1310358CrossRefPubMedPubMedCentralGoogle Scholar
  66. Kunigelis KE, Graner MW (2015) The dichotomy of tumor exosomes (TEX) in cancer immunity: is it all in the ConTeXt? Vaccines 3:1019–1051CrossRefPubMedPubMedCentralGoogle Scholar
  67. Labiano S, Palazon A, Bolanos E, Azpilikueta A, Sanchez-Paulete AR, Morales-Kastresana A, Quetglas JI, Perez-Gracia JL, Gurpide A, Rodriguez-Ruiz M, Aznar MA, Jure-Kunkel M, Berraondo P, Melero I (2016) Hypoxia-induced soluble CD137 in malignant cells blocks CD137L-costimulation as an immune escape mechanism. Oncoimmunology 5:e1062967CrossRefGoogle Scholar
  68. Lan J, Sun L, Xu F, Liu L, Hu F, Song D, Hou Z, Wu W, Luo X, Wang J, Yuan X, Hu J, Wang G (2019) M2 macrophage-derived exosomes promote cell migration and invasion in colon cancer. Can Res 79:146–158CrossRefGoogle Scholar
  69. Lawrence T (2009) The nuclear factor NF-κB pathway in inflammation. Cold Spring Harb Perspect Biol 1:a001651CrossRefPubMedPubMedCentralGoogle Scholar
  70. Lehmann BD, Paine MS, Brooks AM, McCubrey JA, Renegar RH, Wang R, Terrian DM (2008) Senescence-associated exosome release from human prostate cancer cells. Can Res 68:7864–7871CrossRefGoogle Scholar
  71. Lespagnol A, Duflaut D, Beekman C, Blanc L, Fiucci G, Marine JC, Vidal M, Amson R, Telerman A (2008) Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in tsap6/steap3-null mice. Cell Death Differ 15:1723–1733CrossRefGoogle Scholar
  72. Lin LY, Yang L, Zeng Q, Wang L, Chen ML, Zhao ZH, Ye GD, Luo QC, Lv PY, Guo QW, Li BA, Cai JC, Cai WY (2018) Tumor-originated exosomal lncUEGC1 as a circulating biomarker for early-stage gastric cancer. Mol Cancer 17:84CrossRefPubMedPubMedCentralGoogle Scholar
  73. Lindenbergh MFS, Koerhuis DGJ, Borg EGF, van ‘t Veld EM, Driedonks TAP, Wubbolts R, Stoorvogel W, Boes M (2019) Bystander T-cells support clonal T-cell activation by controlling the release of dendritic cell-derived immune-stimulatory extracellular vesicles. Front Immunol 10:448Google Scholar
  74. Liu H, Chen L, Liu J, Meng H, Zhang R, Ma L, Wu L, Yu S, Shi F, Li Y, Zhang L, Wang L, Feng S, Zhang Q, Peng Y, Wu Q, Liu C, Chang X, Yang L, Uemura Y, Yu X, Liu T (2017) Co-delivery of tumor-derived exosomes with alpha-galactosylceramide on dendritic cell-based immunotherapy for glioblastoma. Cancer Lett 411:182–190CrossRefGoogle Scholar
  75. Magistrelli G, Jeannin P, Herbault N, Benoit De Coignac A, Gauchat JF, Bonnefoy JY, Delneste Y (1999) A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells. Eur J Immunol 29:3596–3602Google Scholar
  76. Marleau AM, Chen CS, Joyce JA, Tullis RH (2012) Exosome removal as a therapeutic adjuvant in cancer. J Transl Med 10:134CrossRefPubMedPubMedCentralGoogle Scholar
  77. Mathivanan S, Simpson RJ (2009) Exocarta: a compendium of exosomal proteins and RNA. Proteomics 9:4997–5000CrossRefGoogle Scholar
  78. Matsumura T, Sugimachi K, Iinuma H, Takahashi Y, Kurashige J, Sawada G, Ueda M, Uchi R, Ueo H, Takano Y, Shinden Y, Eguchi H, Yamamoto H, Doki Y, Mori M, Ochiya T, Mimori K (2015) Exosomal microRNA in serum is a novel biomarker of recurrence in human colorectal cancer. Br J Cancer 113:275–281CrossRefPubMedPubMedCentralGoogle Scholar
  79. Medrano RFV, Hunger A, Mendonca SA, Barbuto JAM, Strauss BE (2017) Immunomodulatory and antitumor effects of type I interferons and their application in cancer therapy. Oncotarget 8:71249–71284CrossRefPubMedPubMedCentralGoogle Scholar
  80. Mezzadra R, Sun C, Jae LT, Gomez-Eerland R, de Vries E, Wu W, Logtenberg MEW, Slagter M, Rozeman EA, Hofland I, Broeks A, Horlings HM, Wessels LFA, Blank CU, Xiao Y, Heck AJR, Borst J, Brummelkamp TR, Schumacher TNM (2017) Identification of CMTM6 and CMTM4 as PD-L1 protein regulators. Nature 549:106–110CrossRefPubMedPubMedCentralGoogle Scholar
  81. 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 167:6736–6744CrossRefGoogle Scholar
  82. Monypenny J, Milewicz H, Flores-Borja F, Weitsman G, Cheung A, Chowdhury R, Burgoyne T, Arulappu A, Lawler K, Barber PR, Vicencio JM, Keppler M, Wulaningsih W, Davidson SM, Fraternali F, Woodman N, Turmaine M, Gillett C, Franz D, Quezada SA, Futter CE, Von Kriegsheim A, Kolch W, Vojnovic B, Carlton JG, Ng T (2018) ALIX regulates tumor-mediated immunosuppression by controlling EGFR activity and PD-L1 presentation. Cell Rep 24:630–641CrossRefPubMedPubMedCentralGoogle Scholar
  83. Nguyen KB, Salazar-Mather TP, Dalod MY, Van Deusen JB, Wei XQ, Liew FY, Caligiuri MA, Durbin JE, Biron CA (2002) Coordinated and distinct roles for IFN-αβ, IL-12, and IL-15 regulation of NK cell responses to viral infection. J Immunol 169:4279–4287CrossRefGoogle Scholar
  84. 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 5:9993CrossRefPubMedPubMedCentralGoogle Scholar
  85. 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 11:1155–1160CrossRefGoogle Scholar
  86. Nishida-Aoki N, Tominaga N, Takeshita F, Sonoda H, Yoshioka Y, Ochiya T (2017) Disruption of circulating extracellular vesicles as a novel therapeutic strategy against cancer metastasis. Mol Ther J Am Soc Gene Ther 25:181–191CrossRefGoogle Scholar
  87. Noy R, Pollard JW (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41:49–61CrossRefPubMedPubMedCentralGoogle Scholar
  88. Oaks MK, Hallett KM, Penwell RT, Stauber EC, Warren SJ, Tector AJ (2000) A native soluble form of CTLA-4. Cell Immunol 201:144–153CrossRefGoogle Scholar
  89. Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, Moita CF, Schauer K, Hume AN, Freitas RP, Goud B, Benaroch P, Hacohen N, Fukuda M, Desnos C, Seabra MC, Darchen F, Amigorena S, Moita LF, Thery C (2010) Rab27a and rab27b control different steps of the exosome secretion pathway. Nat Cell Biol 12:19–30, sup pp 11–13Google Scholar
  90. Pan BT, Johnstone RM (1983) Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: Selective externalization of the receptor. Cell 33:967–978CrossRefGoogle Scholar
  91. Park JE, Dutta B, Tse SW, Gupta N, Tan CF, Low JK, Yeoh KW, Kon OL, Tam JP, Sze SK (2019) Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microrna-mediated metabolic shift. Oncogene 38:5158–5173CrossRefGoogle Scholar
  92. Pathan M, Fonseka P, Chitti SV, Kang T, Sanwlani R, Van Deun J, Hendrix A, Mathivanan S (2019) Vesiclepedia 2019: a compendium of rna, proteins, lipids and metabolites in extracellular vesicles. Nucleic Acids Res 47:D516–D519CrossRefGoogle Scholar
  93. Peterson MF, Otoc N, Sethi JK, Gupta A, Antes TJ (2015) Integrated systems for exosome investigation. Methods 87:31–45CrossRefGoogle Scholar
  94. Piao YJ, Kim HS, Hwang EH, Woo J, Zhang M, Moon WK (2018) Breast cancer cell-derived exosomes and macrophage polarization are associated with lymph node metastasis. Oncotarget 9:7398–7410CrossRefGoogle Scholar
  95. Pitt JM, Charrier M, Viaud S, Andre F, Besse B, Chaput N, Zitvogel L (2014) Dendritic cell-derived exosomes as immunotherapies in the fight against cancer. J Immunol 193:1006–1011CrossRefGoogle Scholar
  96. Pitt JM, Andre F, Amigorena S, Soria JC, Eggermont A, Kroemer G, Zitvogel L (2016) Dendritic cell-derived exosomes for cancer therapy. J Clin Investig 126:1224–1232CrossRefGoogle Scholar
  97. Poggio M, Hu T, Pai CC, Chu B, Belair CD, Chang A, Montabana E, Lang UE, Fu Q, Fong L, Blelloch R (2019) Suppression of exosomal PD-L1 induces systemic anti-tumor immunity and memory. Cell 177(414–427):e413Google Scholar
  98. Qin X, Guo H, Wang X, Zhu X, Yan M, Wang X, Xu Q, Shi J, Lu E, Chen W, Zhang J (2019) Exosomal miR-196a derived from cancer-associated fibroblasts confers cisplatin resistance in head and neck cancer through targeting CDKN1b and ING5. Genome Biol 20:12CrossRefPubMedPubMedCentralGoogle Scholar
  99. Qu L, Ding J, Chen C, Wu ZJ, Liu B, Gao Y, Chen W, Liu F, Sun W, Li XF, Wang X, Wang Y, Xu ZY, Gao L, Yang Q, Xu B, Li YM, Fang ZY, Xu ZP, Bao Y, Wu DS, Miao X, Sun HY, Sun YH, Wang HY, Wang LH (2016) Exosome-transmitted lncARSR promotes sunitinib resistance in renal cancer by acting as a competing endogenous RNA. Cancer Cell 29:653–668CrossRefGoogle Scholar
  100. Raposo G, Stoorvogel W (2013) Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 200:373–383CrossRefPubMedPubMedCentralGoogle Scholar
  101. Rayamajhi S, Nguyen TDT, Marasini R, Aryal S (2019) Macrophage-derived exosome-mimetic hybrid vesicles for tumor targeted drug delivery. Acta Biomater 94:482–494CrossRefGoogle Scholar
  102. Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, Joshua AM, Patnaik A, Hwu WJ, Weber JS, Gangadhar TC, Hersey P, Dronca R, Joseph RW, Zarour H, Chmielowski B, Lawrence DP, Algazi A, Rizvi NA, Hoffner B, Mateus C, Gergich K, Lindia JA, Giannotti M, Li XN, Ebbinghaus S, Kang SP, Robert C (2016) Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA 315:1600–1609CrossRefGoogle Scholar
  103. Richards KE, Zeleniak AE, Fishel ML, Wu J, Littlepage LE, Hill R (2017) Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene 36:1770–1778CrossRefGoogle Scholar
  104. Ricklefs FL, Alayo Q, Krenzlin H, Mahmoud AB, Speranza MC, Nakashima H, Hayes JL, Lee K, Balaj L, Passaro C, Rooj AK, Krasemann S, Carter BS, Chen CC, Steed T, Treiber J, Rodig S, Yang K, Nakano I, Lee H, Weissleder R, Breakefield XO, Godlewski J, Westphal M, Lamszus K, Freeman GJ, Bronisz A, Lawler SE, Chiocca EA (2018) Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles. Sci Adv 4:eaar2766Google Scholar
  105. Rincon-Orozco B, Kunzmann V, Wrobel P, Kabelitz D, Steinle A, Herrmann T (2005) Activation of V gamma 9V delta 2 T cells by NKG2D. J Immunol 175:2144–2151CrossRefGoogle Scholar
  106. Ringuette Goulet C, Bernard G, Tremblay S, Chabaud S, Bolduc S, Pouliot F (2018) Exosomes induce fibroblast differentiation into cancer-associated fibroblasts through TGFβ signaling. Mol Cancer Res MCR 16:1196–1204CrossRefGoogle Scholar
  107. Rossille D, Gressier M, Damotte D, Maucort-Boulch D, Pangault C, Semana G, Le Gouill S, Haioun C, Tarte K, Lamy T, Milpied N, Fest T, Groupe Ouest-Est des Leucemies et Autres Maladies du S (2014) High level of soluble programmed cell death ligand 1 in blood impacts overall survival in aggressive diffuse large B-cell lymphoma: results from a French multicenter clinical trial. Leukemia 28:2367–2375Google Scholar
  108. Ruiz-Lopez L, Blancas I, Garrido JM, Mut-Salud N, Moya-Jodar M, Osuna A, Rodriguez-Serrano F (2018) The role of exosomes on colorectal cancer: a review. J Gastroenterol Hepatol 33:792–799CrossRefGoogle Scholar
  109. Saito Y, Ohnishi K, Miyashita A, Nakahara S, Fujiwara Y, Horlad H, Motoshima T, Fukushima S, Jinnin M, Ihn H, Takeya M, Komohara Y (2015) Prognostic significance of CD169 + lymph node sinus macrophages in patients with malignant melanoma. Cancer Immunol Res 3:1356–1363CrossRefGoogle Scholar
  110. Saunderson SC, McLellan AD (2017) Role of lymphocyte subsets in the immune response to primary B cell-derived exosomes. J Immunol 199:2225–2235CrossRefGoogle Scholar
  111. Schmittgen TD (2019) Exosomal miRNA cargo as mediator of immune escape mechanisms in neuroblastoma. Can Res 79:1293–1294CrossRefGoogle Scholar
  112. Seo N, Shirakura Y, Tahara Y, Momose F, Harada N, Ikeda H, Akiyoshi K, Shiku H (2018) Activated CD8(+) T cell extracellular vesicles prevent tumour progression by targeting of lesional mesenchymal cells. Nat Commun 9:435CrossRefPubMedPubMedCentralGoogle Scholar
  113. 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:e1500845CrossRefPubMedPubMedCentralGoogle Scholar
  114. Shenoy GN, Loyall J, Maguire O, Iyer V, Kelleher RJ Jr, Minderman H, Wallace PK, Odunsi K, Balu-Iyer SV, Bankert RB (2018) Exosomes associated with human ovarian tumors harbor a reversible checkpoint of T-cell responses. Cancer Immunol Res 6:236–247CrossRefPubMedPubMedCentralGoogle Scholar
  115. Shi M, Jiang Y, Yang L, Yan S, Wang YG, Lu XJ (2018) Decreased levels of serum exosomal miR-638 predict poor prognosis in hepatocellular carcinoma. J Cell Biochem 119:4711–4716CrossRefGoogle Scholar
  116. Shifrin N, Raulet DH, Ardolino M (2014) NK cell self tolerance, responsiveness and missing self recognition. Semin Immunol 26:138–144CrossRefPubMedPubMedCentralGoogle Scholar
  117. Shrestha S, Yang K, Guy C, Vogel P, Neale G, Chi H (2015) T reg cells require the phosphatase PTEN to restrain TH1 and T FH cell responses. Nat Immunol 16:178–187CrossRefPubMedPubMedCentralGoogle Scholar
  118. Skokos D, Botros HG, Demeure C, Morin J, Peronet R, Birkenmeier G, Boudaly S, Mecheri S (2003) Mast cell-derived exosomes induce phenotypic and functional maturation of dendritic cells and elicit specific immune responses in vivo. J Immunol 170:3037–3045CrossRefGoogle Scholar
  119. 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-β1. Haematologica 96:1302–1309CrossRefPubMedPubMedCentralGoogle Scholar
  120. Takahashi A, Okada R, Nagao K, Kawamata Y, Hanyu A, Yoshimoto S, Takasugi M, Watanabe S, Kanemaki MT, Obuse C, Hara E (2017) Exosomes maintain cellular homeostasis by excreting harmful DNA from cells. Nat Commun 8:15287CrossRefPubMedPubMedCentralGoogle Scholar
  121. Tauro BJ, Greening DW, Mathias RA, Ji H, Mathivanan S, Scott AM, Simpson RJ (2012) Comparison of ultracentrifugation, density gradient separation, and immunoaffinity capture methods for isolating human colon cancer cell line lim1863-derived exosomes. Methods 56:293–304CrossRefGoogle Scholar
  122. Theodoraki MN, Yerneni SS, Hoffmann TK, Gooding WE, Whiteside TL (2018) Clinical significance of PD-L1(+) exosomes in plasma of head and neck cancer patients. Clin Cancer Res 24:896–905 An official Journal of the American Association for Cancer ResearchCrossRefGoogle Scholar
  123. Topalian SL, Taube JM, Anders RA, Pardoll DM (2016) Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 16:275–287CrossRefPubMedPubMedCentralGoogle Scholar
  124. Torralba D, Baixauli F, Villarroya-Beltri C, Fernandez-Delgado I, Latorre-Pellicer A, Acin-Perez R, Martin-Cofreces NB, Jaso-Tamame AL, Iborra S, Jorge I, Gonzalez-Aseguinolaza G, Garaude J, Vicente-Manzanares M, Enriquez JA, Mittelbrunn M, Sanchez-Madrid F (2018) Priming of dendritic cells by DNA-containing extracellular vesicles from activated T cells through antigen-driven contacts. Nat Commun 9:2658CrossRefPubMedPubMedCentralGoogle Scholar
  125. Van Deun J, Hendrix A, Consortium E-T (2017) Is your article ev-tracked? J Extracellular Vesicles 6:1379835Google Scholar
  126. 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-15Rα. PLoS ONE 4:e4942CrossRefPubMedPubMedCentralGoogle Scholar
  127. Wahlgren J, Karlson Tde L, Glader P, Telemo E, Valadi H (2012) Activated human t cells secrete exosomes that participate in IL-2 mediated immune response signaling. PLoS ONE 7:e49723CrossRefPubMedPubMedCentralGoogle Scholar
  128. 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 Investig 116:2521–2531PubMedGoogle Scholar
  129. Wang T, Gilkes DM, Takano N, Xiang L, Luo W, Bishop CJ, Chaturvedi P, Green JJ, Semenza GL (2014) Hypoxia-inducible factors and rab22a mediate formation of microvesicles that stimulate breast cancer invasion and metastasis. Proc Natl Acad Sci USA 111:3234–3242CrossRefGoogle Scholar
  130. Wang L, Wang H, Chen H, Wang WD, Chen XQ, Geng QR, Xia ZJ, Lu Y (2015) Serum levels of soluble programmed death ligand 1 predict treatment response and progression free survival in multiple myeloma. Oncotarget 6:41228–41236PubMedPubMedCentralGoogle Scholar
  131. Wang J, Sanmamed MF, Datar I, Su TT, Ji L, Sun J, Chen L, Chen Y, Zhu G, Yin W, Zheng L, Zhou T, Badri T, Yao S, Zhu S, Boto A, Sznol M, Melero I, Vignali DAA, Schalper K, Chen L (2019a) Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell 176(334–347):e312Google Scholar
  132. Wang X, Qin X, Yan M, Shi J, Xu Q, Li Z, Yang W, Zhang J, Chen W (2019b) Loss of exosomal miR-3188 in cancer-associated fibroblasts contributes to HNC progression. J Exper Clin Cancer Res CR 38:151CrossRefGoogle Scholar
  133. Ward FJ, Dahal LN, Wijesekera SK, Abdul-Jawad SK, Kaewarpai T, Xu H, Vickers MA, Barker RN (2013) The soluble isoform of CTLA-4 as a regulator of T-cell responses. Eur J Immunol 43:1274–1285CrossRefGoogle Scholar
  134. Whiteside TL (2013) Immune modulation of T-cell and NK (natural killer) cell activities by TEXs (tumour-derived exosomes). Biochem Soc Trans 41:245–251CrossRefPubMedPubMedCentralGoogle Scholar
  135. Wieckowski EU, 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 lymphocytes. J Immunol 183:3720–3730CrossRefPubMedPubMedCentralGoogle Scholar
  136. 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 7:297–303CrossRefGoogle Scholar
  137. 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-C2β. FEBS Lett 589:1911–1919CrossRefGoogle Scholar
  138. Xu W, Yang Z, Lu N (2016) From pathogenesis to clinical application: insights into exosomes as transfer vectors in cancer. J Exper Clin Cancer Res CR. 35:156CrossRefGoogle Scholar
  139. Yan W, Chang Y, Liang X, Cardinal JS, Huang H, Thorne SH, Monga SP, Geller DA, Lotze MT, Tsung A (2012) High-mobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases. Hepatology 55:1863–1875CrossRefPubMedPubMedCentralGoogle Scholar
  140. Yang M, Chen J, Su F, Yu B, Su F, Lin L, Liu Y, Huang JD, Song E (2011) Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Mol Cancer 10:117CrossRefPubMedPubMedCentralGoogle Scholar
  141. 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 GADD45α. Mol Cancer 14:190CrossRefPubMedPubMedCentralGoogle Scholar
  142. Yang Y, Li CW, Chan LC, Wei Y, Hsu JM, Xia W, Cha JH, Hou J, Hsu JL, Sun L, Hung MC (2018) Exosomal PD-L1 harbors active defense function to suppress T cell killing of breast cancer cells and promote tumor growth. Cell Res 28:862–864CrossRefPubMedPubMedCentralGoogle Scholar
  143. Yang J, Bi L, He X, Wang Z, Qian Y, Xiao L, Shi B (2019) Follicular helper T cell derived exosomes promote B cell proliferation and differentiation in antibody-mediated rejection after renal transplantation. Biomed Res Int 2019:6387924PubMedPubMedCentralGoogle Scholar
  144. 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 5:5439–5452CrossRefPubMedPubMedCentralGoogle Scholar
  145. Ye L, Zhang Q, Cheng Y, Chen X, Wang G, Shi M, Zhang T, Cao Y, Pan H, Zhang L, Wang G, Deng Y, Yang Y, Chen G (2018) Tumor-derived exosomal HMGB1 fosters hepatocellular carcinoma immune evasion by promoting TIM-1(+) regulatory B cell expansion. J Immunother Cancer 6:145CrossRefPubMedPubMedCentralGoogle Scholar
  146. Yin Y, Cai X, Chen X, Liang H, Zhang Y, Li J, Wang Z, Chen X, Zhang W, Yokoyama S, Wang C, Li L, Li L, Hou D, Dong L, Xu T, Hiroi T, Yang F, Ji H, Zhang J, Zen K, Zhang CY (2014) Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth. Cell Res 24:1164–1180CrossRefPubMedPubMedCentralGoogle Scholar
  147. Ying X, Wu Q, Wu X, Zhu Q, Wang X, Jiang L, Chen X, Wang X (2016) Epithelial ovarian cancer-secreted exosomal miR-222-3p induces polarization of tumor-associated macrophages. Oncotarget 7:43076–43087PubMedPubMedCentralGoogle Scholar
  148. Yu X, Harris SL, Levine AJ (2006) The regulation of exosome secretion: a novel function of the p53 protein. Can Res 66:4795–4801CrossRefGoogle Scholar
  149. Yu J, Lin Y, Xiong X, Li K, Yao Z, Dong H, Jiang Z, Yu D, Yeung SJ, Zhang H (2019) Detection of exosomal PD-L1 RNA in saliva of patients with periodontitis. Front Genet 10:202CrossRefPubMedPubMedCentralGoogle Scholar
  150. Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, Torrejon DY, Abril-Rodriguez G, Sandoval S, Barthly L, Saco J, Homet Moreno B, Mezzadra R, Chmielowski B, Ruchalski K, Shintaku IP, Sanchez PJ, Puig-Saus C, Cherry G, Seja E, Kong X, Pang J, Berent-Maoz B, Comin-Anduix B, Graeber TG, Tumeh PC, Schumacher TN, Lo RS, Ribas A (2016) Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med 375:819–829CrossRefPubMedPubMedCentralGoogle Scholar
  151. Zhao R, Zhang Y, Zhang X, Yang Y, Zheng X, Li X, Liu Y, Zhang Y (2018) Exosomal long noncoding RNA HOTTIP as potential novel diagnostic and prognostic biomarker test for gastric cancer. Mol Cancer 17:68CrossRefPubMedPubMedCentralGoogle Scholar
  152. 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 292:65–69CrossRefGoogle Scholar
  153. Zhou J, Mahoney KM, Giobbie-Hurder A, Zhao F, Lee S, Liao X, Rodig S, Li J, Wu X, Butterfield LH, Piesche M, Manos MP, Eastman LM, Dranoff G, Freeman GJ, Hodi FS (2017) Soluble PD-L1 as a biomarker in malignant melanoma treated with checkpoint blockade. Cancer Immunol Res 5:480–492CrossRefPubMedPubMedCentralGoogle Scholar
  154. Zhu X, Shen H, Yin X, Yang M, Wei H, Chen Q, Feng F, Liu Y, Xu W, Li Y (2019) Macrophages derived exosomes deliver miR-223 to epithelial ovarian cancer cells to elicit a chemoresistant phenotype. J Exper Clin Cancer Res CR 38:81CrossRefGoogle Scholar
  155. Zitvogel L, Galluzzi L, Kepp O, Smyth MJ, Kroemer G (2015) Type I interferons in anticancer immunity. Nat Rev Immunol 15:405–414CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  1. 1.Department of Gastroenterology, Xinhua HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
  2. 2.Women’s Cancer ProgramSamuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterLos AngelesUSA
  3. 3.Department of Cardiology, Xinhua HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
  4. 4.Smidt Heart Institute, Cedars-Sinai Medical CenterLos AngelesUSA
  5. 5.The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine of Ministry of Education, School and Hospital of StomatologyWuhan UniversityWuhanPeople’s Republic of China

Personalised recommendations