The cellular process of exosome shedding turns out to have a wide range of important regulatory functions. Their original discovery in sheep reticulocyte maturation gave rise to the idea that exosomes may function as a trash bin for unnecessary and redundant proteins, which, at the time, offered an alternative pathway for lysosome degradation [1]. Nevertheless, most attention has been given to their role in supporting the immune system. Functional in vivo experiments have shown that exosomes affect the immune system by expressing and processing surface antigens.
The cellular process of exosome shedding turns out to have a wide range of important regulatory functions. Their original discovery in sheep reticulocyte maturation gave rise to the idea that exosomes may function as a trash bin for unnecessary and redundant proteins, which, at the time, offered an alternative pathway for lysosome degradation [1].
Nevertheless, most attention has been given to their role in supporting the immune system. Functional in vivo experiments have shown that exosomes affect the immune system by expressing and processing surface antigens.
The discovery came in two pieces. First, exosomes are enriched with specific antigens, as compared to other whole-cell lysates.
Second, exosomes from antigen-presenting cells (APCs), such as dendritic cells, contain large amounts of major histocompatibility complex (MHC) class I and II molecules. When APC-derived exosomes are incubated with donor cells, MHC could be re-expressed in these cells triggering the desired immune response [2].
Results like these indicate that there is an exchange of membranes or membrane proteins between exosomes and cells and that, as a result, exosomes harbor an innate ability to communicate with other cells.
Studies conducted in 2010 correlated with previous studies indicating exosomes bear highly specific antigens on their surface indicating its identity to other cells [3]. Antigens are unique proteins for each individual and are produced by the MHC genes [4]. If the antigens of the cell are rejected (because the cell is an invader from another body), the bodies B- and T-cells are activated, and the cell is obliterated. If the invading cell has no antigens at all, NK immunity cells are triggered, which bind to the invading cell and induce apoptosis. If the antigens on the cell surface are down-regulated but not altogether eliminated, a foreign cell is able to elude the host's immune system. Some infectious agents, notably members of the herpes virus family, downregulate MHC expression on infected cells to avoid detection by T- cells [5]. This seems to be the case in at least one type of cancer, canine transmissible venereal tumor, where its antigens are downregulated as its method of tumor dispersal [6].
Aside from the membrane transfer, exosomes contain proteins and RNAs that can also be shuttled between cells through exosomes. By transferring RNAs, exosomes are capable of transferring genetic information that can later be translated into functional proteins in target cells [7]. In the field of cancer research, there is an ongoing debate regarding the exact role of exosomes, and if they function as pro- or anti-tumor responders.
Experiments in mice have shown that cancer-derived exosomes can induce a protective immune response. It has also been demonstrated that exosomes isolated from malignant effusions are an effective source of tumor antigens that can be presented to CD8+ cytotoxic T-cells in the form of a drug or vaccine [8].
Studies conducted on the exosomes of dendritic cells, called Dex, showed that mice immunized with Dex fitted with Toxoplasma gondii antigen were protected against T. gondii infection [9]. Dex can also directly trigger the activation of NK cells in mice, as well as, cancer patients [10]. The first phase I clinical trial revealed that Dex vaccines significantly improve the number of circulating NK cells and other NK-dependant functions in a majority of the cancer patients studied [11].
Thus, exosomes are a powerful new tool in the arsenal to deal with cancer cells and disease.
Currently, the most extensive studies on exosomes are being conducted at the Gustave Roussy and Curie Institutes in France, who are both studying exosomes from patients with cancer. Phase II clinical studies are already under way to test the immunological benefits of Dex in patients with inoperable non-small cell lung cancer (NSCLC) [12]. Additionally, preclinical studies have shown that peptide vaccines have a higher anti-tumor efficacy when carried by exosomes [13]. The stability of exosomes, particularly Dex, also makes it possible to load exosomes with specific targeting molecules that are only damaging to the cancer, and not to normal cells.
Exosome research is an exciting opportunity that will allow us to reach much further into the fields of personalized medicine.
This field has many opportunities and hurdles to overcome. NIH has recognized the enormous potential exosomes, and has recently granted $130 million to cancer therapy [14].
SOURCES
Images come courtesy of SystemBioscienes.com and The-Scientist.com, respectively.
[1,2] Duijvesz, D., et al, Exosomes as Biomarker Treasure Chests for Prostate Cancer, European Urology, V 59, 2011, pp 823-831.
[3,4,10,12,13] Viaud, S., Thery, C. Ploix S., Dendritic Cell-Derived Exosomes for Cancer Immunotherapy: What's Next?. Cancer Research, February 9, 2010.
[5] Natural Killer Cells. Immunology for Medical Students. By Roderick Nairn and Matthew Helbert. 2nd edition. Published by Elsevier. <https://www.inkling.com/read/immunology-for-medical-students-nairn-helbert-2nd/chapter-21/natural-killer-cells>. [September 27, 2014].
[6] Lui, CC, Wang YS, Lin CY, et al: Transient downregulation of monocyte-derived dendritic-cell differentiation, function, and survival during tumoral progression and regression in an in vivo canine model of transmissible venereal tumor. Cancer Immunology and Immunotherapy. 57:479-491, 2008.
[7] Keller, S., et al, Exosomes: From biogenesis and secretion to biological function, Immunology Letters 107 (2006) 102-108.
[8] Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, Geuze HJ: B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996, 183:116172.
[9, Aline F., Bout D, Amigorena S., Roingeard P., Dimier-Posson I. Toxo-plasma gondii antigen-pulsed-dendritic cell-derived exosomes induce a protective immune response against T. gondii infection. Infect Immun, 2004;72:4127-37.
[11] Viaud S., Terme M., Flament C., et al. Dendritic cell-derived exosomes promote naturall killer cell activation and proliferation: a role for NKG2D ligands and IL-15Ralpha. PLoS One 2009;4e4942.
[14] NINDS Funding Strategy-FY 2014. NIH. <http://www.ninds.nih.gov/funding/ninds_funding_strategy.htm>. [September, 26, 2014].