Berhanu, Aklile
(2005)
COMBINATIONAL CYTOKINE THERAPY OF CANCER: PLEIOTROPIC IMPACT WITHIN THE TUMOR MICROENVIRONMENT.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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.
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| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
1 September 2005 |
| Date Type: |
Completion |
| Defense Date: |
10 August 2005 |
| Approval Date: |
1 September 2005 |
| Submission Date: |
17 August 2005 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Cancer Therapy; Cytotoxic T Lymphocytes; Dendritic Cells; Flt3 Ligand; GM-CSF; Regulatory T cells; Tummor Immunity; Tumor Infiltrating Leukocytes |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-08172005-124835/, etd-08172005-124835 |
| Date Deposited: |
10 Nov 2011 19:59 |
| Last Modified: |
19 Dec 2016 14:37 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9143 |
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