Studies demonstrating the ability of in vitro generated dendritic cells (DCs) to successfully mediate anti-tumor efficacy when used as therapeutic vaccines suggest that treatments capable of promoting in situ DC-mediated cross-priming events may exhibit at least a comparable degree of clinical effectiveness. As a result, I assessed whether optimizing the number of DCs within the tumor microenvironment would improve the cross-priming of tumor-reactive T cells, resulting in improved therapeutic benefit. I observed that the treatment of CMS4-bearing BALB/c mice with the combination of Flt3 ligand (FL) and GM-CSF for five sequential days is sufficient to optimize the number of tumor-infiltrating DCs and to result in the enhanced systemic priming of tumor-specific CD8+ T cells that are consequently recruited into the tumor microenvironment. Despite these preferred immunologic endpoints, combinational FL and GM-CSF treatment failed to impact the growth of established CMS4, RENCA or CT26 tumors. The observation that large numbers of CD4+ T cells also infiltrate tumors in mice treated with combinations of FL and GM-CSF prompted me to explore whether CD4+ regulatory T cells might play an active role in mediating the suppression of co-infiltrating tumor-specific CD8+ T cells. Indeed, I found that nearly half of the tumor-associated CD4+ T cells expressed the Foxp3 protein and significantly suppressed the proliferation of naïve allo-reactive CD4+ T cells and the IFN- production by tumor-specific CD8+ T cells in vitro. Moreover, I found that combinational FL and GM-CSF treatment induced significant expansion of Foxp3+CD4+ T cells in the spleens of treated animals, regardless of tumor-bearing status. Consistent with the suppressive effects of tumor-associated CD4+ T cells on combined FL and GM-CSF-based therapy, the in vivo depletion of CD4+ T cells resulted in a marked inhibition of tumor growth in treated mice that was dependent on the presence of CD8+ T cells. My findings have important implications in cancer therapy as they demonstrate that suppression mediated by regulatory T cells can present a major roadblock for the successful implementation of immunotherapeutic approaches to treat cancers.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-08172005-124835 |
| Date | 01 September 2005 |
| Creators | Berhanu, Aklile |
| Contributors | Simon M. Barratt-Boyes, DVM, Ph.D., Albert B. DeLeo, Ph.D., Walter J. Storkus, Ph.D., Paul D. Robbins, Ph.D., Angus W. Thomson, Ph.D., D.Sc. |
| 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-08172005-124835/ |
| Rights | unrestricted, 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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