Tumor cells usually express specific antigens that are potentially immunogenic; however, established tumors primarily induce immune tolerance. In the last decade, a population of small membrane vesicles, termed "exosomes", has gained increasing attention for their potential role in tumor immune regulation. Exosomes are formed in the late endocytic compartments and are released upon their fusion with the plasma membrane. They are secreted by various cell types, especially tumor cells and cells in the hematopoietic system. Although tumor-derived exosomes usually contain tumor antigens, they have been shown to exert diverse immunosuppressive effects. However, the ability of tumor-derived exosomes to induce antigen-specific immunosuppression has not been well examined. Also, the immunoregulatory effect of exosome-like vesicles in the blood circulation of tumor-bearing hosts remains unclear.
<br><br>In this thesis, we first investigate the role of tumor-derived exosomes in mediating antigen-specific immune suppression using ovalbumin (OVA) as a model tumor antigen. We demonstrate that exosomes derived from OVA-expressing tumor cell lines potently suppress OVA-specific delayed-type hypersensitivity (DTH) response. We also show that exosomes are mostly taken up by dendritic cells (DCs) after local administration, and the mRNA levels of TGF-beta1 and IL-4 in the draining lymph node were significantly elevated in correlation with suppression of the DTH response. Furthermore, tumor-derived exosomes affect the function of DCs in vitro by inhibiting their maturation and inducing TGF-beta1 production. These results suggest that tumor-derived exosomes are able to confer antigen-specific immune suppression possibly by DC-mediated mechanism.
<br><br>We further investigate the immunoregulatory effect of plasma-derived exosomes and demonstrate that plasma-derived exosomes isolated from mice bearing OVA-expressing tumors are able to suppress the OVA-specific DTH response. However, enrichment of tumor-derived exosomes in blood plasma was not identified and the suppressive effect is partially mediated by the MHC class II+ vesicle portion. The third part of the thesis discusses the B cell stimulatory and the consequent T cell inhibitory effect of exosomes derived from tumor cells with mycoplasma infection.
<br><br>The work presented in this thesis increases our understanding of the immunoregulatory role of tumor-derived exosomes, circulating exosomes in tumor-bearing hosts as well as exosomes derived from pathogen-infected tumor cells.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-11052010-232050 |
| Date | 19 November 2010 |
| Creators | Yang, Chenjie |
| Contributors | Christine A. Milcarek, Adrian E. Morelli, Paul D. Robbins, Martin C. Schmidt, Walter J. Storkus, Russell D. Salter |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-11052010-232050/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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