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Extracellular vesicles in immunomodulation and tumor progression

Abstract

Extracellular vesicles have emerged as prominent regulators of the immune response during tumor progression. EVs contain a diverse repertoire of molecular cargo that plays a critical role in immunomodulation. Here, we identify the role of EVs as mediators of communication between cancer and immune cells. This expanded role of EVs may shed light on the mechanisms behind tumor progression and provide translational diagnostic and prognostic tools for immunologists.

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Fig. 1: Heterogeneous cargo of EVs.
Fig. 2: Mechanisms of EV immune regulation.
Fig. 3: Cancer EVs directly regulate tumor progression.
Fig. 4: Potential clinical translations for EVs.

References

  1. Yáñez-mó, M. et al. Biological properties of extracellular vesicles and their physiological functions. J. Extracell. Vesicles 4, 27066 (2015).

    PubMed  Article  Google Scholar 

  2. Colombo, M., Raposo, G. & Théry, C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol. 30, 255–289 (2014).

    CAS  PubMed  Article  Google Scholar 

  3. Kalra, H., Drummen, G. P. C. & Mathivanan, S. Focus on extracellular vesicles: Introducing the next small big thing. Int. J. Mol. Sci. 17, 170 (2016).

  4. Raposo, G. & Stoorvogel, W. Extracellular vesicles: exosomes, microvesicles, and friends. J. Cell Biol. 200, 373–383 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Théry, C. et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J. Extracell. Vesicles 7, 1535750 (2018).

  6. Niel, G. Van, Angelo, G. D. & Raposo, G. Shedding light on the cell biology of extracellular vesicles. Nat. Rev. Mol. Cell Biol. 19, 213–228 (2018).

    PubMed  Article  CAS  Google Scholar 

  7. Xu, R. et al. Extracellular vesicles in cancer—implications for future improvements in cancer care. Nat. Rev. Clin. Oncol. 15, 617–638 (2018).

    CAS  PubMed  Article  Google Scholar 

  8. Becker, A. et al. Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell 30, 836–848 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Raposo, G. et al. B lymphocytes secrete antigen-presenting vesicles. J. Exp. Med. 183, 1161–1172 (1996).

    CAS  PubMed  Article  Google Scholar 

  10. Zitvogel, L. et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat. Med. 4, 594–600 (1998).

    CAS  PubMed  Article  Google Scholar 

  11. Théry, C. et al. Indirect activation of naïve CD4+ T cells by dendritic cell-derived exosomes. Nat. Immunol. 3, 1156–1162 (2002).

    PubMed  Article  CAS  Google Scholar 

  12. Mallegol, J. et al. T84-intestinal epithelial exosomes bear MHC class II/peptide complexes potentiating antigen presentation by dendritic cells. Gastroenterology 132, 1866–1876 (2007).

    CAS  PubMed  Article  Google Scholar 

  13. Admyre, C. et al. Exosomes with major histocompatibility complex class II and co-stimulatory molecules are present in human BAL fluid. Eur. Respir. J. 22, 578–583 (2003).

    CAS  PubMed  Article  Google Scholar 

  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. 89, 125–131 (2003).

    CAS  PubMed  Article  Google Scholar 

  15. Clayton, A. et al. Analysis of antigen presenting cell derived exosomes, based on immuno-magnetic isolation and flow cytometry. J. Immunol. Methods 247, 163–174 (2001).

    CAS  PubMed  Article  Google Scholar 

  16. Lynch, S. et al. Novel MHC class I structures on exosomes. J. Immunol. 183, 1884–1891 (2009).

    CAS  PubMed  Article  Google Scholar 

  17. Bobrie, A., Colombo, M., Raposo, G. & Théry, C. Exosome secretion: molecular mechanisms and roles in immune responses. Traffic 12, 1659–1668 (2011).

    CAS  PubMed  Article  Google Scholar 

  18. Hwang, I., Shen, X. & Sprent, J. Direct stimulation of naïve T cells by membrane vesicles from antigen-presenting cells: Distinct roles for CD54 and B7 molecules. Proc. Natl Acad. Sci. USA 100, 6670–6675 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. Alexander, M. et al. Exosome-delivered microRNAs modulate the inflammatory response to endotoxin. Nat. Cell Biol. 6, 7321 (2015).

  20. Admyre, C., Johansson, S. M., Paulie, S. & Gabrielsson, S. Direct exosome stimulation of peripheral human T cells detected by ELISPOT. Eur. J. Immunol. 36, 1772–1781 (2006).

    CAS  PubMed  Article  Google Scholar 

  21. Fitzgerald, W. et al. A system of cytokines encapsulated in extracellular vesicles. Sci. Rep. 8, 8973 (2018).

  22. Qazi, K. R., Gehrmann, U., Jordo, E. D., Karlsson, M. C. I. & Gabrielsson, S. Antigen-loaded exosomes alone induce TH1-type memory through a B cell–dependent mechanism. Immunobiology 113, 2673–2683 (2009).

    CAS  Google Scholar 

  23. Tkach, M. et al. Qualitative differences in T‐cell activation by dendritic cell‐derived extracellular vesicle subtypes. EMBO J. 36, 3012–3028 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Vincent-Schneider, H. Exosomes bearing HLA-DR1 molecules need dendritic cells to efficiently stimulate specific T cells. Int. Immunol. 14, 713–722 (2002).

    CAS  PubMed  Article  Google Scholar 

  25. Ruhland, M. K. et al. Visualizing synaptic transfer of tumor antigens among dendritic cells. Cancer Cell 37, 786–799.e5 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. Alvarez-Jiménez, V. D. et al. Extracellular vesicles released from mycobacterium tuberculosis-infected neutrophils promote macrophage autophagy and decrease intracellular mycobacterial survival. Front. Immunol. 9, 272 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. Danesh, A. et al. Granulocyte-derived extracellular vesicles activate monocytes and are associated with mortality in intensive care unit patients. Front. Immunol. 9, 956 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. Xu, Y. et al. Macrophages transfer antigens to dendritic cells by releasing exosomes containing dead-cell-associated antigens partially through a ceramide-dependent pathway to enhance CD4+ T-cell responses. Immunology 149, 157–171 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Becker, P. D. et al. B lymphocytes contribute to indirect pathway T cell sensitisation via acquisition of extracellular vesicles. Am. J. Transplant. https://doi.org/10.1111/ajt.16088 (2020).

  30. Zeng, F. & Morelli, A. E. Extracellular vesicle-mediated MHC cross-dressing in immune homeostasis, transplantation, infectious diseases, and cancer. Semin. Immunopathol. 40, 477–490 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Huang, L. et al. Exosomes from thymic stromal lymphopoietin-activated dendritic cells promote Th2 differentiation through the OX40 ligand. Pathobiology 86, 111–117 (2019).

    CAS  PubMed  Article  Google Scholar 

  32. Kremer, A. N. et al. Natural T-cell ligands that are created by genetic variants can be transferred between cells by extracellular vesicles. Eur. J. Immunol. 48, 1621–1631 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Wei, G. et al. Dendritic cells derived exosomes migration to spleen and induction of inflammation are regulated by CCR7. Sci. Rep. 7, 42996 (2017).

  34. Schierer, S. et al. Extracellular vesicles from mature dendritic cells (DC) differentiate monocytes into immature DC. Life Sci. Alliance 1, e201800093 (2018).

  35. Kowal, J. et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc. Natl Acad. Sci. USA 113, E968–E977 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. Cui, X. et al. Thyrocyte-derived exosome-targeted dendritic cells stimulate strong CD4+ T lymphocyte responses. Mol. Cell. Endocrinol. 506, 110756 (2020).

    CAS  PubMed  Article  Google Scholar 

  37. Cai, Z. et al. Immunosuppressive exosomes from TGF-$β$1 gene-modified dendritic cells attenuate Th17-mediated inflammatory autoimmune disease by inducing regulatory T cells. Cell Res. 22, 607–610 (2012).

    CAS  PubMed  Article  Google Scholar 

  38. Zhang, M. et al. Inhibition of MicroRNA let-7 depresses maturation and functional state of dendritic cells in response to lipopolysaccharide stimulation via targeting suppressor of cytokine signaling 1. J. Immunol. 187, 1674–1683 (2011).

    CAS  PubMed  Article  Google Scholar 

  39. Lindenbergh, M. F. S. et al. Bystander T-cells support clonal T-cell activation by controlling the release of dendritic cell-derived immune-stimulatory extracellular vesicles. Front. Immunol. 10, 448 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Torralba, D. et al. Priming of dendritic cells by DNA-containing extracellular vesicles from activated T cells through antigen-driven contacts. Nat. Commun. 9, 2658 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. Chiou, N. et al. Selective export into extracellular vesicles and function of tRNA fragments during T cell activation. Cell Rep. 25, 3356–3370.e4 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Segura, E., Amigorena, S. & The, C. Mature dendritic cells secrete exosomes with strong ability to induce antigen-specific effector immune responses. Blood Cells, Mol. Dis. 35, 89–93 (2005).

    CAS  Article  Google Scholar 

  43. Kaur, S. et al. CD63, MHC class 1, and CD47 identify subsets of extracellular vesicles containing distinct populations of noncoding RNAs. Sci. Rep. 8, 2577 (2018).

  44. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor a-chains (CD25). J. Immunol. 155, 1151–1165 (1995).

    CAS  PubMed  Google Scholar 

  45. Tung, S. L. et al. Regulatory T cell-derived extracellular vesicles modify dendritic cell function. Sci. Rep. 8, 6065 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  46. Tung, S. L. et al. Regulatory T cell extracellular vesicles modify T-effector cell cytokine production and protect against human skin allograft damage. Front. Cell Dev. Biol. 8, 317 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  47. Aiello, S. et al. Extracellular vesicles derived from T regulatory cells suppress T cell proliferation and prolong allograft survival. Sci. Rep. 7, 11518 (2017).

  48. Okoye, I. S. et al. MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells. Immunity 41, 89–103 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Torri, A. et al. Extracellular MicroRNA signature of human helper T cell subsets in health and autoimmunity. J. Biol. Chem. 292, 2903–2915 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. Chen, L. et al. Exosomes derived from T regulatory cells suppress CD8+ cytotoxic T lymphocyte proliferation and prolong liver allograft survival. Med. Sci. Monit. 25, 4877–4884 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Naqvi, A. R., Fordham, J. B., Ganesh, B. & Nares, S. MiR-24, miR-30b and miR-142-3p interfere with antigen processing and presentation by primary macrophages and dendritic cells. Sci. Rep. 6, 1–12 (2016).

    Article  CAS  Google Scholar 

  52. Sullivan, J. A. et al. Treg-cell-derived IL-35-coated extracellular vesicles promote infectious tolerance. Cell Rep. 30, 1039–1051.e5 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Turnis, M. E. et al. Interleukin-35 limits anti-tumor immunity. Immunity 44, 316–329 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Kim, S. H., Bianco, N. R., Shufesky, W. J., Morelli, A. E. & Robbins, P. D. MHC class II+ exosomes in plasma suppress inflammation in an antigen-specific and fas ligand/fas-dependent manner. J. Immunol. 179, 2235–2241 (2007).

    CAS  PubMed  Article  Google Scholar 

  55. Kim, S. H. et al. Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive. Mol. Ther. 13, 289–300 (2006).

    CAS  PubMed  Article  Google Scholar 

  56. O Reilly, L. A. et al. Membrane-bound Fas ligand only is essential for Fas-induced apoptosis. Nature 461, 659–663 (2009).

    CAS  Article  Google Scholar 

  57. Monleón, I. et al. 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, 6736–6744 (2001).

    PubMed  Article  Google Scholar 

  58. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Article  Google Scholar 

  59. Hiratsuka, S., Watanabe, A., Aburatani, H. & Maru, Y. Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat. Cell Biol. 8, 1369–1375 (2006).

    CAS  PubMed  Article  Google Scholar 

  60. Oskarsson, T. et al. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat. Med. 17, 867–874 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Kano, A. Tumor cell secretion of soluble factor(s) for specific immunosuppression. Sci. Rep. 5, 8913 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Hoshino, A. et al. Tumour exosome integrins determine organotropic metastasis. Nature 527, 329 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Muller, L., Mitsuhashi, M., Simms, P., Gooding, W. E. & Whiteside, T. L. Tumor-derived exosomes regulate expression of immune function-related genes in human T cell subsets. Sci. Rep. 6, 20254 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  65. Capello, M. et al. Exosomes harbor B cell targets in pancreatic adenocarcinoma and exert decoy function against complement-mediated cytotoxicity. Nat. Commun. 10, 254 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. Mahaweni, N. M., Kaijen-Lambers, M. E. H., Dekkers, J., Aerts, J. G. J. V. & Hegmans, J. P. J. J. Tumour-derived exosomes as antigen delivery carriers in dendritic cell-based immunotherapy for malignant mesothelioma. J. Extracell. Vesicles 2, 22492 (2013).

    Article  CAS  Google Scholar 

  67. Peinado, H. et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat. Med. 18, 883–891 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Costa-Silva, B. et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell Biol. 17, 816–826 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Chen, G. et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560, 382–386 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. Czystowska-Kuzmicz, M. et al. Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma. Nat. Commun. 10, 3000 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. Ricklefs, F. L. et al. Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles. Sci. Adv. 4, eaar2766 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. Haderk, F. et al. Tumor-derived exosomes modulate PD-L1 expression in monocytes. Sci. Immunol. 2, 28 (2017).

    Article  Google Scholar 

  73. Karwacz, K. et al. PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells. EMBO Mol. Med. 3, 581–592 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Daassi, D., Mahoney, K. M. & Freeman, G. J. The importance of exosomal PDL1 in tumour immune evasion. Nat. Rev. Immunol. 20, 209–215 (2020).

    CAS  PubMed  Article  Google Scholar 

  75. Vignard, V. et al. MicroRNAs in tumor exosomes drive immune escape in melanoma. Cancer Immunol. Res. 8, 255–267 (2020).

    CAS  PubMed  Article  Google Scholar 

  76. Rodriguez, P. C. et al. Regulation of T cell receptor CD3ζ chain expression byl-Arginine. J. Biol. Chem. 277, 21123–21129 (2002).

    CAS  PubMed  Article  Google Scholar 

  77. Van De Velde, L. A. et al. T cells encountering myeloid cells rogrammed for amino acid-dependent immunosuppression use Rictor/mTORC2 protein for proliferative checkpoint decisions. J. Biol. Chem. 292, 15–30 (2017).

    PubMed  Article  CAS  Google Scholar 

  78. Rodriguez, P. C., Quiceno, D. G. & Ochoa, A. C. l-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109, 1568–1573 (2006).

    PubMed  Article  CAS  Google Scholar 

  79. Salimu, J. et al. Dominant immunosuppression of dendritic cell function by prostate-cancer-derived exosomes. J. Extracell. Vesicles 6, 1368823 (2017).

  80. Hsu, Y. L. et al. Hypoxic lung-cancer-derived extracellular vesicle microRNA-103a increases the oncogenic effects of macrophages by targeting PTEN. Mol. Ther. 26, 568–581 (2018).

    CAS  PubMed  Article  Google Scholar 

  81. de Jong, O. G. et al. Cellular stress conditions are reflected in the protein and RNA content of endothelial cell-derived exosomes. J. Extracell. Vesicles 1, https://doi.org/10.3402/jev.v1i0.18396 (2012).

  82. Park, J. E. et al. Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNA-mediated metabolic shift. Oncogene 38, 5158–5173 (2019).

    CAS  PubMed  Article  Google Scholar 

  83. Lenzini, S., Bargi, R., Chung, G. & Shin, J.-W. Matrix mechanics and water permeation regulate extracellular vesicle transport. Nat. Nanotechnol. 15, 217–223 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. Gilkes, D. M., Semenza, G. L. & Wirtz, D. Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nat. Rev. Cancer 14, 430–439 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. Diaz, B. & Yuen, A. The impact of hypoxia in pancreatic cancer invasion and metastasis. Hypoxia 2, 91 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  86. Berchem, G. et al. Hypoxic tumor-derived microvesicles negatively regulate NK cell function by a mechanism involving TGF-β and miR23a transfer. Oncoimmunology 5, e1062968 (2016).

  87. Kim, D.-H. & Wirtz, D. Cytoskeletal tension induces the polarized architecture of the nucleus. Biomaterials 48, 161–172 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Fraley, S. I., Feng, Y., Giri, A., Longmore, G. D. & Wirtz, D. Dimensional and temporal controls of three-dimensional cell migration by zyxin and binding partners. Nat. Commun. 3, 719 (2012).

    PubMed  Article  CAS  Google Scholar 

  89. Khatau, S. B. et al. A perinuclear actin cap regulates nuclear shape. Proc. Natl Acad. Sci. 106, 19017–19022 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. Wirtz, D., Konstantopoulos, K. & Searson, P. C. The physics of cancer: The role of physical interactions and mechanical forces in metastasis. Nat. Rev. Cancer 11, 512–522 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. Follain, G. et al. Fluids and their mechanics in tumour transit: shaping metastasis. Nat. Rev. Cancer 20, 107–124 (2020).

    CAS  PubMed  Article  Google Scholar 

  92. Dionisi, M. et al. Tumor-derived microvesicles enhance cross-processing ability of clinical grade dendritic cells. Front. Immunol. 9, 2481 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  93. Huang, F., Wan, J., Hu, W. & Hao, S. Enhancement of anti-leukemia immunity by leukemia-derived exosomes via downregulation of TGF-β1 expression. Cell. Physiol. Biochem. 44, 240–254 (2017).

    PubMed  Article  Google Scholar 

  94. Rughetti, A. et al. Microvesicle cargo of tumor-associated MUC1 to dendritic cells allows cross-presentation and specific carbohydrate processing. Cancer Immunol. Res. 2, 177–186 (2014).

    CAS  PubMed  Article  Google Scholar 

  95. Kitai, Y. et al. DNA-containing exosomes derived from cancer cells treated with topotecan activate a STING-dependent pathway and reinforce antitumor immunity. J. Immunol. 198, 1649–1659 (2017).

    CAS  PubMed  Article  Google Scholar 

  96. Lin, W. et al. Radiation-induced small extracellular vesicles as ‘carriages’ promote tumor antigen release and trigger antitumor immunity. Theranostics 10, 4871–4884 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. Squadrito, M. L., Cianciaruso, C., Hansen, S. K. & De Palma, M. EVIR: chimeric receptors that enhance dendritic cell cross-dressing with tumor antigens. Nat. Methods 15, 183–186 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. Zhang, H. et al. Cell-free tumor microparticle vaccines stimulate dendritic cells via cGAS/STING signaling. Cancer Immunol. Res. 3, 196–205 (2015).

    CAS  PubMed  Article  Google Scholar 

  99. Caruso Bavisotto, C. et al. Immunomorphological pattern of molecular chaperones in normal and pathological thyroid tissues and circulating exosomes: Potential use in clinics. Int. J. Mol. Sci. 20, 4496 (2019).

    PubMed Central  Article  CAS  Google Scholar 

  100. Diamond, J. M. et al. Exosomes shuttle TREX1-sensitive IFN-stimulatory dsDNA from irradiated cancer cells to DCs. Cancer Immunol. Res. 6, 910–920 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. Ma, J. et al. Mechanisms by which dendritic cells present tumor microparticle antigens to CD8+ T cells. Cancer Immunol. Res. 6, 1057–1069 (2018).

    CAS  PubMed  Article  Google Scholar 

  102. Jeppesen, D. K. et al. Reassessment of exosome composition. Cell 177, 428–445.e18 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. Menay, F. et al. Exosomes isolated from ascites of T-cell lymphoma-bearing mice expressing surface CD24 and HSP-90 induce a tumor-specific immune response. Front. Immunol. 8, 286 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  104. Daßler-Plenker, J. et al. RIG-I activation induces the release of extracellular vesicles with antitumor activity. Oncoimmunology 5, e1219827 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  105. Gastpar, R. et al. Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res. 65, 5238–5247 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. Li, Q. et al. Bifacial effects of engineering tumour cell-derived exosomes on human natural killer cells. Exp. Cell. Res. 363, 141–150 (2018).

    CAS  PubMed  Article  Google Scholar 

  107. Greening, D. W., Gopal, S. K., Xu, R., Simpson, R. J. & Chen, W. Exosomes and their roles in immune regulation and cancer. Semin. Cell Developmental Biol. 40, 72–81 (2015).

    CAS  Article  Google Scholar 

  108. Scholl, J. N. et al. Characterization and antiproliferative activity of glioma-derived extracellular vesicles. Nanomedicine 15, 1001–1018 (2020).

    CAS  PubMed  Article  Google Scholar 

  109. Salamon, P., Mekori, Y. A. & Shefler, I. Lung cancer-derived extracellular vesicles: a possible mediator of mast cell activation in the tumor microenvironment. Cancer Immunol. Immunother. 69, 373–381 (2020).

    CAS  PubMed  Article  Google Scholar 

  110. Pucci, F. et al. SCS macrophages suppress melanoma by restricting tumor-derived vesicle–B cell interactions. Science 352, 242–246 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. Seo, N. et al. Activated CD8+ T cell extracellular vesicles prevent tumour progression by targeting of lesional mesenchymal cells. Nat. Commun. 9, 435 (2018).

  112. Peters, P. J. et al. Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes. J. Exp. Med. 173, 1099–1109 (1991).

    CAS  PubMed  Article  Google Scholar 

  113. Lu, Z. et al. Dendritic cell-derived exosomes elicit tumor regression in autochthonous hepatocellular carcinoma mouse models. J. Hepatol. 67, 739–748 (2017).

    CAS  PubMed  Article  Google Scholar 

  114. Ostheimer, C., Gunther, S., Bache, M., Vordermark, D. & Multhoff, G. Dynamics of heat shock protein 70 serum levels as a predictor of clinical response in non-small-cell lung cancer and correlation with the hypoxia-related marker osteopontin. Front. Immunol. 8, 1305 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  115. Gao, Y. et al. Enhancing the treatment effect on melanoma by heat shock protein 70-peptide complexes purified from human melanoma cell lines. Oncol. Rep. 36, 1243–1250 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. Blachere, B. N. E. et al. Heat shock protein—peptide complexes, reconstituted in. J. Exp. Med. 186, 1315–1322 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. Ochyl, L. J. et al. PEGylated tumor cell membrane vesicles as a new vaccine platform for cancer immunotherapy. Biomaterials 182, 157–166 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. Koh, E. et al. Exosome–SIRPα, a CD47 blockade increases cancer cell phagocytosis. Biomaterials 121, 121–129 (2017).

    CAS  PubMed  Article  Google Scholar 

  119. Kamerkar, S. et al. Therapeutic targeting of oncogenic KRAS in pancreatic cancer by engineered exosomes. Nature 546, 498–503 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. Rana, S., Yue, S., Stadel, D. & Zöller, M. Toward tailored exosomes: the exosomal tetraspanin web contributes to target cell selection. Int. J. Biochem. Cell Biol. 44, 1574–1584 (2012).

    CAS  PubMed  Article  Google Scholar 

  121. Sun, H. et al. A multifunctional liposomal nanoplatform co-delivering hydrophobic and hydrophilic doxorubicin for complete eradication of xenografted tumors. Nanoscale 11, 17759–17772 (2019).

    CAS  PubMed  Article  Google Scholar 

  122. Watson, D. C. et al. Efficient production and enhanced tumor delivery of engineered extracellular vesicles. Biomaterials 105, 195–205 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. Whitford, W. & Guterstam, P. Exosome manufacturing status. Future Med. Chem. 11, 1225–1236 (2019).

    CAS  PubMed  Article  Google Scholar 

  124. Zhao, Z., McGill, J., Gamero-Kubota, P. & He, M. Microfluidic on-demand engineering of exosomes towards cancer immunotherapy. Lab Chip 19, 1877–1886 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. Luan, X. et al. Engineering exosomes as refined biological nanoplatforms for drug delivery. Acta Pharmacol. Sin. 38, 754–763 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. Zhou, H. et al. Collection, storage, preservation, and normalization of human urinary exosomes for biomarker discovery. Kidney Int. 69, 1471–1476 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. Jeyaram, A. & Jay, S. M. Preservation and storage stability of extracellular vesicles for therapeutic applications. AAPS J. 20, 1–7 (2018).

    CAS  Article  Google Scholar 

  128. Shimabukuro-Vornhagen, A. et al. Cytokine release syndrome. J. Immunother. Cancer 6, 56 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  129. Asadirad, A. et al. Phenotypical and functional evaluation of dendritic cells after exosomal delivery of miRNA-155. Life Sci. 219, 152–162 (2019).

    CAS  PubMed  Article  Google Scholar 

  130. Dusoswa, S. A. et al. Glycan modification of glioblastoma-derived extracellular vesicles enhances receptor-mediated targeting of dendritic cells. J. Extracell. Vesicles 8, 1648995 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. Gu, X., Erb, U., Büchler, M. W. & Zöller, M. Improved vaccine efficacy of tumor exosome compared to tumor lysate loaded dendritic cells in mice. Int. J. Cancer 136, E74–E84 (2015).

    CAS  PubMed  Article  Google Scholar 

  132. Rossowska, J. et al. Antitumor potential of extracellular vesicles released by genetically modified murine colon carcinoma cells with overexpression of interleukin-12 and shRNA for TGF-β1. Front. Immunol. 10, 211 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. Matsumoto, A., Takahashi, Y., Ariizumi, R., Nishikawa, M. & Takakura, Y. Development of DNA-anchored assembly of small extracellular vesicle for efficient antigen delivery to antigen presenting cells. Biomaterials 225, 119518 (2019).

    CAS  PubMed  Article  Google Scholar 

  134. Morishita, M., Takahashi, Y., Nishikawa, M., Ariizumi, R. & Takakura, Y. Enhanced class I tumor antigen presentation via cytosolic delivery of exosomal cargos by tumor-cell-derived exosomes displaying a pH-sensitive fusogenic peptide. Mol. Pharm. 14, 4079–4086 (2017).

    CAS  PubMed  Article  Google Scholar 

  135. Zuo, B. et al. Alarmin-painted exosomes elicit persistent antitumor immunity in large established tumors in mice. Nat. Commun. 11, 1–16 (2020).

    Google Scholar 

  136. Al-Samadi, A. et al. Crosstalk between tongue carcinoma cells, extracellular vesicles, and immune cells in in vitro and in vivo models. Oncotarget 8, 60123–60134 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  137. Morishita, M., Takahashi, Y., Matsumoto, A., Nishikawa, M. & Takakura, Y. Exosome-based tumor antigens–adjuvant co-delivery utilizing genetically engineered tumor cell-derived exosomes with immunostimulatory CpG DNA. Biomaterials 111, 55–65 (2016).

    CAS  PubMed  Article  Google Scholar 

  138. Huang, F. et al. TGF-β1-silenced leukemia cell-derived exosomes target dendritic cells to induce potent anti-leukemic immunity in a mouse model. Cancer Immunol. Immunother. 66, 1321–1331 (2017).

    CAS  PubMed  Article  Google Scholar 

  139. Guo, D. et al. Exosomes from heat-stressed tumour cells inhibit tumour growth by converting regulatory T cells to TH17 cells via IL-6. Immunology 154, 132–143 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. Gobbo, J. et al. Restoring anticancer immune response by targeting tumor-derived exosomes with a HSP70 peptide aptamer. J. Natl Cancer Inst. 108, 1–11 (2016).

    Article  CAS  Google Scholar 

  141. Bell, B. M., Kirk, I. D., Hiltbrunner, S., Gabrielsson, S. & Bultema, J. J. Designer exosomes as next-generation cancer immunotherapy. Nanomed. Nanotechnol. Biol. Med. 12, 163–169 (2016).

    CAS  Article  Google Scholar 

  142. Pitt, J. M. et al. Dendritic cell-derived exosomes for cancer therapy. J. Clin. Invest. 126, 1224–1232 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  143. Tran, T. H., Mattheolabakis, G., Aldawsari, H. & Amiji, M. Exosomes as nanocarriers for immunotherapy of cancer and inflammatory diseases. Clin. Immunol. 160, 46–58 (2015).

    CAS  PubMed  Article  Google Scholar 

  144. Besse, B. et al. Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC. Oncoimmunology 5, e1071008 (2016).

    PubMed  Article  CAS  Google Scholar 

  145. Chen, S. et al. Poly(I:C) enhanced anti-cervical cancer immunities induced by dendritic cells-derived exosomes. Int. J. Biol. Macromol. 113, 1182–1187 (2018).

    CAS  PubMed  Article  Google Scholar 

  146. Matsumoto, A., Asuka, M., Takahashi, Y. & Takakura, Y. Antitumor immunity by small extracellular vesicles collected from activated dendritic cells through effective induction of cellular and humoral immune responses. Biomaterials 252, 120112 (2020).

    CAS  PubMed  Article  Google Scholar 

  147. Zhu, L. et al. Novel alternatives to extracellular vesicle-based immunotherapy–exosome mimetics derived from natural killer cells. Artif. Cells, Nanomed. Biotechnol. 46, S166–S179 (2018).

    CAS  Article  Google Scholar 

  148. Zhu, L. et al. Exosomes derived from natural killer cells exert therapeutic effect in melanoma. Theranostics 7, 2732–2745 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. Zhu, L. et al. Enhancement of antitumor potency of extracellular vesicles derived from natural killer cells by IL-15 priming. Biomaterials 190–191, 38–50 (2019).

    PubMed  Article  CAS  Google Scholar 

  150. Lee, H., Park, H., Noh, G. J. & Lee, E. S. pH-responsive hyaluronate-anchored extracellular vesicles to promote tumor-targeted drug delivery. Carbohydr. Polym. 202, 323–333 (2018).

    CAS  PubMed  Article  Google Scholar 

  151. Meng, X. et al. Diagnostic and prognostic relevance of circulating exosomal miR-373, miR-200a, miR-200b and miR-200c in patients with epithelial ovarian cancer. Adv. Exp. Med. Biol. 924, 3–8 (2016).

    CAS  PubMed  Article  Google Scholar 

  152. Maji, S. et al. Exosomal annexin II promotes angiogenesis and breast cancer metastasis. Mol. Cancer Res. 15, 93–105 (2017).

    CAS  PubMed  Article  Google Scholar 

  153. Muller, L. et al. Exosomes isolated from plasma of glioma patients enrolled in a vaccination trial reflect antitumor immune activity and might predict survival. Oncoimmunology 4, e1008347 (2015).

  154. Ciravolo, V. et al. Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy. J. Cell. Physiol. 227, 658–667 (2012).

    CAS  PubMed  Article  Google Scholar 

  155. Battke, C. et al. Tumour exosomes inhibit binding of tumour-reactive antibodies to tumour cells and reduce ADCC. Cancer Immunol. Immunother. 60, 639–648 (2011).

    CAS  PubMed  Article  Google Scholar 

  156. Cordonnier, M. et al. Tracking the evolution of circulating exosomal-PD-L1 to monitor melanoma patients. J. Extracell. Vesicles 9, 1710899 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

This work was supported through grants from the National Institutes of Health (T32GM008764) to C.M. and the National Cancer Institute (U54CA143868) and the National Institute on Aging (U01AG060903) to D.W. Figures designed with BioRender.com.

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Marar, C., Starich, B. & Wirtz, D. Extracellular vesicles in immunomodulation and tumor progression. Nat Immunol 22, 560–570 (2021). https://doi.org/10.1038/s41590-021-00899-0

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