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Berhanu, Aklile (2005) COMBINATIONAL CYTOKINE THERAPY OF CANCER: PLEIOTROPIC IMPACT WITHIN THE TUMOR MICROENVIRONMENT. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairStorkus, Walter Jstorkuswj@upmc.eduSTORKUSW
Committee MemberDeLeo, Albert Bdeleo@pitt.eduDELEO
Committee MemberThomson, Angus Wthomsonaw@upmc.eduATHOMSON
Committee MemberRobbins, Paul Dprobb@pitt.eduPROBB
Committee MemberBarratt-Boyes, Simon Msmbb@pitt.eduSMBB
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:, etd-08172005-124835
Date Deposited: 10 Nov 2011 19:59
Last Modified: 19 Dec 2016 14:37


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