IMMUNE NETWORK

The Korean Association of Immunobiologists (대한면역학회)
권호 표지
DOI QR코드

DOI QR Code

Exosomal Communication Between the Tumor Microenvironment and Innate Immunity and Its Therapeutic Application

  • Received : 2022.05.23
  • Accepted : 2022.08.18
  • Published : 2022.10.31
Download PDF
⟨ Previous Next ⟩

Abstract

Exosomes, which are well-known nanoscale extracellular vesicles, are multifunctional biomaterials derived from endosomes and perform various functions. The exosome is a critical material in cell-cell communication. In addition, it regulates the pathophysiological conditions of the tumor microenvironment in particular. In the tumor microenvironment, exosomes play a controversial role in supporting or killing cancer by conveying biomaterials derived from parent cells. Innate immunity is a crucial component of the host defense mechanism, as it prevents foreign substances, such as viruses and other microbes and tumorigenesis from invading the body. Early in the tumorigenesis process, the innate immunity explicitly recognizes the tumor via Ags and educates the adaptive immunity to eliminate it. Recent studies have revealed that exosomes regulate immunity in the tumor microenvironment. Tumor-derived exosomes regulate immunity against tumor progression and metastasis. Furthermore, tumor-derived exosomes regulate polarization, differentiation, proliferation, and activation of innate immune cells. Exosomes produced from innate immune cells can inhibit or support tumor progression and metastasis via immune cell activation and direct cancer inhibition. In this study, we investigated current knowledge regarding the communication between tumor-derived exosomes and innate immune cell-derived exosomes (from macrophages, dendritic cells, NK cells, and neutrophils) in the tumor microenvironment. In addition, we discussed the potential development of exosomal immunotherapy using native or engineered exosomes against cancer.

Keywords

Acknowledgement

This work was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korean Government (MSIT) (No. 2021R1F1A106016611, No. 2022R1C1C1013481).

References

  1. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 2013;200:373-383. 
  2. Colombo M, Raposo G, Thery C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol 2014;30:255-289. 
  3. Wu R, Gao W, Yao K, Ge J. Roles of exosomes derived from immune cells in cardiovascular diseases. Front Immunol 2019;10:648. 
  4. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013;39:1-10. 
  5. Kugeratski FG, Kalluri R. Exosomes as mediators of immune regulation and immunotherapy in cancer. FEBS J 2021;288:10-35. 
  6. Zhou X, Xie F, Wang L, Zhang L, Zhang S, Fang M, Zhou F. The function and clinical application of extracellular vesicles in innate immune regulation. Cell Mol Immunol 2020;17:323-334. 
  7. Joshi BS, de Beer MA, Giepmans BNG, Zuhorn IS. Endocytosis of extracellular vesicles and release of their cargo from endosomes. ACS Nano 2020;14:4444-4455.
  8. Verweij FJ, Middeldorp JM, Pegtel DM. Intracellular signaling controlled by the endosomal-exosomal pathway. Commun Integr Biol 2012;5:88-93. 
  9. Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cell Mol Life Sci 2018;75:193-208. 
  10. Kowal J, Tkach M, Thery C. Biogenesis and secretion of exosomes. Curr Opin Cell Biol 2014;29:116-125. 
  11. Keerthikumar S, Chisanga D, Ariyaratne D, Al Saffar H, Anand S, Zhao K, Samuel M, Pathan M, Jois M, Chilamkurti N, et al. Exocarta: a web-based compendium of exosomal cargo. J Mol Biol 2016;428:688-692. 
  12. Andreu Z, Yanez-Mo M. Tetraspanins in extracellular vesicle formation and function. Front Immunol 2014;5:442. 
  13. 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;164:1807-1815. 
  14. Utsugi-Kobukai S, Fujimaki H, Hotta C, Nakazawa M, Minami M. MHC class I-mediated exogenous antigen presentation by exosomes secreted from immature and mature bone marrow derived dendritic cells. Immunol Lett 2003;89:125-131. 
  15. Muntasell A, Berger AC, Roche PA. T cell-induced secretion of MHC class II-peptide complexes on B cell exosomes. EMBO J 2007;26:4263-4272. 
  16. Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, Yu Z, Yang J, Wang B, Sun H, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 2018;560:382-386. 
  17. Shurtleff MJ, Yao J, Qin Y, Nottingham RM, Temoche-Diaz MM, Schekman R, Lambowitz AM. Broad role for YBX1 in defining the small noncoding RNA composition of exosomes. Proc Natl Acad Sci U S A 2017;114:E8987-E8995. 
  18. Wei Z, Batagov AO, Schinelli S, Wang J, Wang Y, El Fatimy R, Rabinovsky R, Balaj L, Chen CC, Hochberg F, et al. Coding and noncoding landscape of extracellular RNA released by human glioma stem cells. Nat Commun 2017;8:1145. 
  19. Shoae-Hassani A, Hamidieh AA, Behfar M, Mohseni R, Mortazavi-Tabatabaei SA, Asgharzadeh S. Nk cell-derived exosomes from NK cells previously exposed to neuroblastoma cells augment the antitumor activity of cytokine-activated NK cells. J Immunother 2017;40:265-276. 
  20. Liu YC, Zou XB, Chai YF, Yao YM. Macrophage polarization in inflammatory diseases. Int J Biol Sci 2014;10:520-529. 
  21. Nonnenmacher Y, Hiller K. Biochemistry of proinflammatory macrophage activation. Cell Mol Life Sci 2018;75:2093-2109. 
  22. Koh TJ, DiPietro LA. Inflammation and wound healing: the role of the macrophage. Expert Rev Mol Med 2011;13:e23. 
  23. Poh AR, Ernst M. Targeting macrophages in cancer: From bench to bedside. Front Oncol 2018;8:49. 
  24. Baig MS, Roy A, Rajpoot S, Liu D, Savai R, Banerjee S, Kawada M, Faisal SM, Saluja R, Saqib U, et al. Tumor-derived exosomes in the regulation of macrophage polarization. Inflamm Res 2020;69:435-451. 
  25. Almatroodi SA, Almatroudi A, Khan AA, Alhumaydhi FA, Alsahli MA, Rahmani AH. Potential therapeutic targets of epigallocatechin gallate (EGCG), the most abundant catechin in green tea, and its role in the therapy of various types of cancer. Molecules 2020;25:25. 
  26. Jang JY, Lee JK, Jeon YK, Kim CW. Exosome derived from epigallocatechin gallate treated breast cancer cells suppresses tumor growth by inhibiting tumor-associated macrophage infiltration and M2 polarization. BMC Cancer 2013;13:421.
  27. Shao Y, Chen T, Zheng X, Yang S, Xu K, Chen X, Xu F, Wang L, Shen Y, Wang T, et al. Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche in liver metastasis. Carcinogenesis 2018;39:1368-1379. 
  28. Xiao M, Zhang J, Chen W, Chen W. M1-like tumor-associated macrophages activated by exosome-transferred THBS1 promote malignant migration in oral squamous cell carcinoma. J Exp Clin Cancer Res 2018;37:143. 
  29. Wang M, Zhao J, Zhang L, Wei F, Lian Y, Wu Y, Gong Z, Zhang S, Zhou J, Cao K, et al. Role of tumor microenvironment in tumorigenesis. J Cancer 2017;8:761-773. 
  30. Chanmee T, Ontong P, Konno K, Itano N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel) 2014;6:1670-1690. 
  31. Piao YJ, Kim HS, Hwang EH, Woo J, Zhang M, Moon WK. Breast cancer cell-derived exosomes and macrophage polarization are associated with lymph node metastasis. Oncotarget 2017;9:7398-7410. 
  32. Li X, Lei Y, Wu M, Li N. Regulation of macrophage activation and polarization by HCC-derived exosomal lncRNA TUC339. Int J Mol Sci 2018;19:2958. 
  33. Takano Y, Masuda T, Iinuma H, Yamaguchi R, Sato K, Tobo T, Hirata H, Kuroda Y, Nambara S, Hayashi N, et al. Circulating exosomal microRNA-203 is associated with metastasis possibly via inducing tumorassociated macrophages in colorectal cancer. Oncotarget 2017;8:78598-78613. 
  34. Cheng L, Wang Y, Huang L. Exosomes from M1-polarized macrophages potentiate the cancer vaccine by creating a pro-inflammatory microenvironment in the lymph node. Mol Ther 2017;25:1665-1675. 
  35. Li Z, Suo B, Long G, Gao Y, Song J, Zhang M, Feng B, Shang C, Wang D. Exosomal miRNA-16-5p derived from M1 macrophages enhances T cell-dependent immune response by regulating PD-L1 in gastric cancer. Front Cell Dev Biol 2020;8:572689. 
  36. Wu XQ, Dai Y, Yang Y, Huang C, Meng XM, Wu BM, Li J. Emerging role of microRNAs in regulating macrophage activation and polarization in immune response and inflammation. Immunology 2016;148:237-248. 
  37. Wang H, Wang L, Pan H, Wang Y, Shi M, Yu H, Wang C, Pan X, Chen Z. Exosomes derived from macrophages enhance aerobic glycolysis and chemoresistance in lung cancer by stabilizing c-Myc via the inhibition of NEDD4L. Front Cell Dev Biol 2021;8:620603. 
  38. Yang Y, Guo Z, Chen W, Wang X, Cao M, Han X, Zhang K, Teng B, Cao J, Wu W, et al. M2 macrophage-derived exosomes promote angiogenesis and growth of pancreatic ductal adenocarcinoma by targeting E2F2. Mol Ther 2021;29:1226-1238. 
  39. Shortman K, Liu YJ. Mouse and human dendritic cell subtypes. Nat Rev Immunol 2002;2:151-161. 
  40. Wculek SK, Cueto FJ, Mujal AM, Melero I, Krummel MF, Sancho D. Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol 2020;20:7-24. 
  41. Gabrilovich D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol 2004;4:941-952. 
  42. Tesone AJ, Svoronos N, Allegrezza MJ, Conejo-Garcia JR. Pathological mobilization and activities of dendritic cells in tumor-bearing hosts: challenges and opportunities for immunotherapy of cancer. Front Immunol 2013;4:435. 
  43. Hosseini R, Asef-Kabiri L, Yousefi H, Sarvnaz H, Salehi M, Akbari ME, Eskandari N. The roles of tumor-derived exosomes in altered differentiation, maturation and function of dendritic cells. Mol Cancer 2021;20:83. 
  44. 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;124:2621-2633.
  45. Grange C, Tapparo M, Tritta S, Deregibus MC, Battaglia A, Gontero P, Frea B, Camussi G. Role of HLA-G and extracellular vesicles in renal cancer stem cell-induced inhibition of dendritic cell differentiation. BMC Cancer 2015;15:1009. 
  46. Vasaturo A, Di Blasio S, Peeters DG, de Koning CC, de Vries JM, Figdor CG, Hato SV. Clinical implications of co-inhibitory molecule expression in the tumor microenvironment for dc vaccination: a game of stop and go. Front Immunol 2013;4:417. 
  47. Truxova I, Kasikova L, Hensler M, Skapa P, Laco J, Pecen L, Belicova L, Praznovec I, Halaska MJ, Brtnicky T, et al. Mature dendritic cells correlate with favorable immune infiltrate and improved prognosis in ovarian carcinoma patients. J Immunother Cancer 2018;6:139. 
  48. Gao J, Qiu X, Li X, Fan H, Zhang F, Lv T, Song Y. Expression profiles and clinical value of plasma exosomal TIM-3 and galectin-9 in non-small cell lung cancer. Biochem Biophys Res Commun 2018;498:409-415. 
  49. Wang M, Cai Y, Peng Y, Xu B, Hui W, Jiang Y. Exosomal LGALS9 in the cerebrospinal fluid of glioblastoma patients suppressed dendritic cell antigen presentation and cytotoxic T-cell immunity. Cell Death Dis 2020;11:896. 
  50. Rong L, Li R, Li S, Luo R. Immunosuppression of breast cancer cells mediated by transforming growth factor-β in exosomes from cancer cells. Oncol Lett 2016;11:500-504. 
  51. He JG, Xie QL, Li BB, Zhou L, Yan D. Exosomes derived from IDO1-overexpressing rat bone marrow mesenchymal stem cells promote immunotolerance of cardiac allografts. Cell Transplant 2018;27:1657-1683. 
  52. Morrissey SM, Yan J. Exosomal PD-L1: roles in tumor progression and immunotherapy. Trends Cancer 2020;6:550-558. 
  53. Tang Y, Zhang P, Wang Y, Wang J, Su M, Wang Y, Zhou L, Zhou J, Xiong W, Zeng Z, et al. The biogenesis, biology, and clinical significance of exosomal PD-L1 in cancer. Front Immunol 2020;11:604. 
  54. Ning Y, Shen K, Wu Q, Sun X, Bai Y, Xie Y, Pan J, Qi C. Tumor exosomes block dendritic cells maturation to decrease the T cell immune response. Immunol Lett 2018;199:36-43. 
  55. Norian LA, Rodriguez PC, O'Mara LA, Zabaleta J, Ochoa AC, Cella M, Allen PM. Tumor-infiltrating regulatory dendritic cells inhibit CD8+ T cell function via L-arginine metabolism. Cancer Res 2009;69:3086-3094. 
  56. Czystowska-Kuzmicz M, Sosnowska A, Nowis D, Ramji K, Szajnik M, Chlebowska-Tuz J, Wolinska E, Gaj P, Grazul M, Pilch Z, et al. Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma. Nat Commun 2019;10:3000. 
  57. Salimu J, Webber J, Gurney M, Al-Taei S, Clayton A, Tabi Z. Dominant immunosuppression of dendritic cell function by prostate-cancer-derived exosomes. J Extracell Vesicles 2017;6:1368823. 
  58. Ding G, Zhou L, Qian Y, Fu M, Chen J, Chen J, Xiang J, Wu Z, Jiang G, Cao L. Pancreatic cancer-derived exosomes transfer miRNAs to dendritic cells and inhibit RFXAP expression via miR-212-3p. Oncotarget 2015;6:29877-29888. 
  59. 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;292:65-69. 
  60. 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;193:1006-1011. 
  61. 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. 
  62. Wei G, Jie Y, Haibo L, Chaoneng W, Dong H, Jianbing Z, Junjie G, Leilei M, Hongtao S, Yunzeng Z, et al. Dendritic cells derived exosomes migration to spleen and induction of inflammation are regulated by CCR7. Sci Rep 2017;7:42996.
  63. Nolte-'t Hoen EN, Buschow SI, Anderton SM, Stoorvogel W, Wauben MH. Activated T cells recruit exosomes secreted by dendritic cells via LFA-1. Blood 2009;113:1977-1981. 
  64. 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;190:2712-2719. 
  65. Romagnoli GG, Zelante BB, Toniolo PA, Migliori IK, Barbuto JA. Dendritic cell-derived exosomes may be a tool for cancer immunotherapy by converting tumor cells into immunogenic targets. Front Immunol 2015;5:692. 
  66. Guan S, Li Q, Liu P, Xuan X, Du Y. Umbilical cord blood-derived dendritic cells loaded with BGC823 tumor antigens and DC-derived exosomes stimulate efficient cytotoxic T-lymphocyte responses and antitumor immunity in vitro and in vivo. Cent Eur J Immunol 2014;39:142-151. 
  67. Munich S, Sobo-Vujanovic A, Buchser WJ, Beer-Stolz D, Vujanovic NL. Dendritic cell exosomes directly kill tumor cells and activate natural killer cells via TNF superfamily ligands. OncoImmunology 2012;1:1074-1083. 
  68. Huntington ND, Cursons J, Rautela J. The cancer-natural killer cell immunity cycle. Nat Rev Cancer 2020;20:437-454. 
  69. Wu SY, Fu T, Jiang YZ, Shao ZM. Natural killer cells in cancer biology and therapy. Mol Cancer 2020;19:120. 
  70. Morvan MG, Lanier LL. NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer 2016;16:7-19. 
  71. Batista IA, Quintas ST, Melo SA. The interplay of exosomes and NK cells in cancer biology. Cancers (Basel) 2021;13:473. 
  72. Vulpis E, Soriani A, Cerboni C, Santoni A, Zingoni A. Cancer exosomes as conveyors of stress-induced molecules: new players in the modulation of NK cell response. Int J Mol Sci 2019;20:611. 
  73. Hosseini R, Sarvnaz H, Arabpour M, Ramshe SM, Asef-Kabiri L, Yousefi H, Akbari ME, Eskandari N. Cancer exosomes and natural killer cells dysfunction: biological roles, clinical significance and implications for immunotherapy. Mol Cancer 2022;21:15. 
  74. Hong CS, Sharma P, Yerneni SS, Simms P, Jackson EK, Whiteside TL, Boyiadzis M. Circulating exosomes carrying an immunosuppressive cargo interfere with cellular immunotherapy in acute myeloid leukemia. Sci Rep 2017;7:14684. 
  75. Liu C, Yu S, Zinn K, Wang J, Zhang L, Jia Y, Kappes JC, Barnes S, Kimberly RP, Grizzle WE, et al. Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. J Immunol 2006;176:1375-1385. 
  76. Liu J, Wu S, Zheng X, Zheng P, Fu Y, Wu C, Lu B, Ju J, Jiang J. Immune suppressed tumor microenvironment by exosomes derived from gastric cancer cells via modulating immune functions. Sci Rep 2020;10:14749. 
  77. Zhao J, Schlosser HA, Wang Z, Qin J, Li J, Popp F, Popp MC, Alakus H, Chon SH, Hansen HP, et al. Tumor-derived extracellular vesicles inhibit natural killer cell function in pancreatic cancer. Cancers (Basel) 2019;11:874. 
  78. Katsiougiannis S, Chia D, Kim Y, Singh RP, Wong DT. Saliva exosomes from pancreatic tumor-bearing mice modulate NK cell phenotype and antitumor cytotoxicity. FASEB J 2017;31:998-1010. 
  79. Hong CS, Funk S, Muller L, Boyiadzis M, Whiteside TL. Isolation of biologically active and morphologically intact exosomes from plasma of patients with cancer. J Extracell Vesicles 2016;5:29289. 
  80. Azambuja JH, Ludwig N, Yerneni S, Rao A, Braganhol E, Whiteside TL. Molecular profiles and immunomodulatory activities of glioblastoma-derived exosomes. Neurooncol Adv 2020;2:vdaa056.
  81. Xia Y, Zhang Q, Zhen Q, Zhao Y, Liu N, Li T, Hao Y, Zhang Y, Luo C, Wu X. Negative regulation of tumor-infiltrating NK cell in clear cell renal cell carcinoma patients through the exosomal pathway. Oncotarget 2017;8:37783-37795. 
  82. Lugini L, Cecchetti S, Huber V, Luciani F, Macchia G, Spadaro F, Paris L, Abalsamo L, Colone M, Molinari A, et al. Immune surveillance properties of human NK cell-derived exosomes. J Immunol 2012;189:2833-2842. 
  83. Jong AY, Wu CH, Li J, Sun J, Fabbri M, Wayne AS, Seeger RC. Large-scale isolation and cytotoxicity of extracellular vesicles derived from activated human natural killer cells. J Extracell Vesicles 2017;6:1294368. 
  84. Zhu L, Kalimuthu S, Gangadaran P, Oh JM, Lee HW, Baek SH, Jeong SY, Lee SW, Lee J, Ahn BC. Exosomes derived from natural killer cells exert therapeutic effect in melanoma. Theranostics 2017;7:2732-2745. 
  85. Di Pace AL, Tumino N, Besi F, Alicata C, Conti LA, Munari E, Maggi E, Vacca P, Moretta L. Characterization of human NK cell-derived exosomes: role of DNAM1 receptor in exosome-mediated cytotoxicity against tumor. Cancers (Basel) 2020;12:661. 
  86. Neviani P, Wise PM, Murtadha M, Liu CW, Wu CH, Jong AY, Seeger RC, Fabbri M. Natural killerderived exosomal miR-186 inhibits neuroblastoma growth and immune escape mechanisms. Cancer Res 2019;79:1151-1164. 
  87. Sun H, Shi K, Qi K, Kong H, Zhang J, Dai S, Ye W, Deng T, He Q, Zhou M. Natural killer cell-derived exosomal miR-3607-3p inhibits pancreatic cancer progression by targeting IL-26. Front Immunol 2019;10:2819. 
  88. Cooper MA, Elliott JM, Keyel PA, Yang L, Carrero JA, Yokoyama WM. Cytokine-induced memory-like natural killer cells. Proc Natl Acad Sci U S A 2009;106:1915-1919. 
  89. Romee R, Rosario M, Berrien-Elliott MM, Wagner JA, Jewell BA, Schappe T, Leong JW, Abdel-Latif S, Schneider SE, Willey S, et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci Transl Med 2016;8:357ra123. 
  90. Paust S, Gill HS, Wang BZ, Flynn MP, Moseman EA, Senman B, Szczepanik M, Telenti A, Askenase PW, Compans RW, et al. Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses. Nat Immunol 2010;11:1127-1135. 
  91. Zhu L, Kalimuthu S, Oh JM, Gangadaran P, Baek SH, Jeong SY, Lee SW, Lee J, Ahn BC. Enhancement of antitumor potency of extracellular vesicles derived from natural killer cells by IL-15 priming. Biomaterials 2019;190-191:38-50. 
  92. Aarsund M, Segers FM, Wu Y, Inngjerdingen M. Comparison of characteristics and tumor targeting properties of extracellular vesicles derived from primary NK cells or NK-cell lines stimulated with IL-15 or IL-12/15/18. Cancer Immunol Immunother 2022;71:2227-2238. 
  93. Coffelt SB, Wellenstein MD, de Visser KE. Neutrophils in cancer: neutral no more. Nat Rev Cancer 2016;16:431-446. 
  94. Zhang X, Shi H, Yuan X, Jiang P, Qian H, Xu W. Tumor-derived exosomes induce N2 polarization of neutrophils to promote gastric cancer cell migration. Mol Cancer 2018;17:146. 
  95. Hwang WL, Lan HY, Cheng WC, Huang SC, Yang MH. Tumor stem-like cell-derived exosomal RNAs prime neutrophils for facilitating tumorigenesis of colon cancer. J Hematol Oncol 2019;12:10. 
  96. Jiao Y, Zhang T, Zhang C, Ji H, Tong X, Xia R, Wang W, Ma Z, Shi X. Exosomal miR-30d-5p of neutrophils induces M1 macrophage polarization and primes macrophage pyroptosis in sepsis-related acute lung injury. Crit Care 2021;25:356. 
  97. Zhang J, Ji C, Zhang H, Shi H, Mao F, Qian H, Xu W, Wang D, Pan J, Fang X, et al. Engineered neutrophil-derived exosome-like vesicles for targeted cancer therapy. Sci Adv 2022;8:eabj8207.
  98. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009;9:162-174. 
  99. Safarzadeh E, Hashemzadeh S, Duijf PH, Mansoori B, Khaze V, Mohammadi A, Kazemi T, Yousefi M, Asadi M, Mohammadi H, et al. Circulating myeloid-derived suppressor cells: an independent prognostic factor in patients with breast cancer. J Cell Physiol 2019;234:3515-3525. 
  100. Youn JI, Nagaraj S, Collazo M, Gabrilovich DI. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol 2008;181:5791-5802. 
  101. Park MJ, Lee SH, Kim EK, Lee EJ, Baek JA, Park SH, Kwok SK, Cho ML. Interleukin-10 produced by myeloid-derived suppressor cells is critical for the induction of Tregs and attenuation of rheumatoid inflammation in mice. Sci Rep 2018;8:3753. 
  102. Kumar V, Cheng P, Condamine T, Mony S, Languino LR, McCaffrey JC, Hockstein N, Guarino M, Masters G, Penman E, et al. CD45 phosphatase inhibits STAT3 transcription factor activity in myeloid cells and promotes tumor-associated macrophage differentiation. Immunity 2016;44:303-315. 
  103. Bruno A, Mortara L, Baci D, Noonan DM, Albini A. Myeloid derived suppressor cells interactions with natural killer cells and pro-angiogenic activities: roles in tumor progression. Front Immunol 2019;10:771. 
  104. Chen Z, Yuan R, Hu S, Yuan W, Sun Z. Roles of the exosomes derived from myeloid-derived suppressor cells in tumor immunity and cancer progression. Front Immunol 2022;13:817942. 
  105. Rashid MH, Borin TF, Ara R, Piranlioglu R, Achyut BR, Korkaya H, Liu Y, Arbab AS. Critical immunosuppressive effect of MDSC-derived exosomes in the tumor microenvironment. Oncol Rep 2021;45:1171-1181. 
  106. Li X, Li Y, Lu W, Chen M, Ye W, Zhang D. The tumor vessel targeting strategy: a double-edged sword in tumor metastasis. Cells 2019;8:1602. 
  107. Lee SH, Jeong D, Han YS, Baek MJ. Pivotal role of vascular endothelial growth factor pathway in tumor angiogenesis. Ann Surg Treat Res 2015;89:1-8. 
  108. Qu X, Zhuang G, Yu L, Meng G, Ferrara N. Induction of Bv8 expression by granulocyte colony-stimulating factor in CD11b+Gr1+ cells: key role of STAT3 signaling. J Biol Chem 2012;287:19574-19584. 
  109. Deng Z, Rong Y, Teng Y, Zhuang X, Samykutty A, Mu J, Zhang L, Cao P, Yan J, Miller D, et al. Exosomes miR-126a released from MDSC induced by DOX treatment promotes lung metastasis. Oncogene 2017;36:639-651. 
  110. Gao F, Xu Q, Tang Z, Zhang N, Huang Y, Li Z, Dai Y, Yu Q, Zhu J. Exosomes derived from myeloid-derived suppressor cells facilitate castration-resistant prostate cancer progression via S100A9/circMID1/miR-506-3p/MID1. J Transl Med 2022;20:346. 
  111. Jiang M, Zhang W, Zhang R, Liu P, Ye Y, Yu W, Guo X, Yu J. Cancer exosome-derived miR-9 and miR-181a promote the development of early-stage MDSCs via interfering with SOCS3 and PIAS3 respectively in breast cancer. Oncogene 2020;39:4681-4694. 
  112. Guo X, Qiu W, Liu Q, Qian M, Wang S, Zhang Z, Gao X, Chen Z, Xue H, Li G. Immunosuppressive effects of hypoxia-induced glioma exosomes through myeloid-derived suppressor cells via the miR-10a/Rora and miR-21/Pten Pathways. Oncogene 2018;37:4239-4259. 
  113. Ren W, Zhang X, Li W, Feng Q, Feng H, Tong Y, Rong H, Wang W, Zhang D, Zhang Z, et al. Exosomal miRNA-107 induces myeloid-derived suppressor cell expansion in gastric cancer. Cancer Manag Res 2019;11:4023-4040. 
  114. Guo X, Qiu W, Wang J, Liu Q, Qian M, Wang S, Zhang Z, Gao X, Chen Z, Guo Q, et al. Glioma exosomes mediate the expansion and function of myeloid-derived suppressor cells through microRNA-29a/Hbp1 and microRNA-92a/Prkar1a pathways. Int J Cancer 2019;144:3111-3126.
  115. Barros FM, Carneiro F, Machado JC, Melo SA. Exosomes and immune response in cancer: friends or foes? Front Immunol 2018;9:730. 
  116. Gutierrez-Vazquez C, Villarroya-Beltri C, Mittelbrunn M, Sanchez-Madrid F. Transfer of extracellular vesicles during immune cell-cell interactions. Immunol Rev 2013;251:125-142. 
  117. Chen H, Chengalvala V, Hu H, Sun D. Tumor-derived exosomes: Nanovesicles made by cancer cells to promote cancer metastasis. Acta Pharm Sin B 2021;11:2136-2149. 
  118. Syn NL, Wang L, Chow EK, Lim CT, Goh BC. Exosomes in cancer nanomedicine and immunotherapy: prospects and challenges. Trends Biotechnol 2017;35:665-676. 
  119. Bell BM, Kirk ID, Hiltbrunner S, Gabrielsson S, Bultema JJ. Designer exosomes as next-generation cancer immunotherapy. Nanomedicine 2016;12:163-169. 
  120. Ha D, Yang N, Nadithe V. Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. Acta Pharm Sin B 2016;6:287-296. 
  121. 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;172:2126-2136. 
  122. 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;16:782-790. 
  123. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010;363:411-422. 
  124. Besse B, Charrier M, Lapierre V, Dansin E, Lantz O, Planchard D, Le Chevalier T, Livartoski A, Barlesi F, Laplanche A, et al. Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC. OncoImmunology 2015;5:e1071008. 
  125. Schreiner B, Mitsdoerffer M, Kieseier BC, Chen L, Hartung HP, Weller M, Wiendl H. Interferon-beta enhances monocyte and dendritic cell expression of B7-H1 (PD-L1), a strong inhibitor of autologous T-cell activation: relevance for the immune modulatory effect in multiple sclerosis. J Neuroimmunol 2004;155:172-182. 
  126. Yi DH, Appel S. Current status and future perspectives of dendritic cell-based cancer immunotherapy. Scand J Immunol 2013;78:167-171. 
  127. Sabado RL, Bhardwaj N. Directing dendritic cell immunotherapy towards successful cancer treatment. Immunotherapy 2010;2:37-56. 
  128. Temchura VV, Tenbusch M, Nchinda G, Nabi G, Tippler B, Zelenyuk M, Wildner O, Uberla K, Kuate S. Enhancement of immunostimulatory properties of exosomal vaccines by incorporation of fusioncompetent G protein of vesicular stomatitis virus. Vaccine 2008;26:3662-3672. 
  129. 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. 
  130. Harding C, Heuser J, Stahl P. Endocytosis and intracellular processing of transferrin and colloidal gold-transferrin in rat reticulocytes: demonstration of a pathway for receptor shedding. Eur J Cell Biol 1984;35:256-263. 
  131. 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) derived-exosomes: results of thefirst phase I clinical trial. J Transl Med 2005;3:10.
  132. Choi SJ, Cho H, Yea K, Baek MC. Immune cell-derived small extracellular vesicles in cancer treatment. BMB Rep 2022;55:48-56. 
  133. Nam GH, Choi Y, Kim GB, Kim S, Kim SA, Kim IS. Emerging prospects of exosomes for cancer treatment: from conventional therapy to immunotherapy. Adv Mater 2020;32:e2002440.