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HUMAN MYELOID-DERIVED SUPPRESSOR CELLS IN CANCER:
INDUCTION, FUNCTIONAL CHARACTERIZATION, AND THERAPY
by
Melissa Genevieve Lechner
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(SYSTEMS BIOLOGY AND DISEASE)
May 2011
Copyright 2011 Melissa Genevieve Lechner
Object Description
| Title | Human myeloid-derived suppressor cells in cancer: Induction, functional characterization, and therapy |
| Author | Lechner, Melissa Genevieve |
| Author email | lechner@usc.edu; melissalechner@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Systems Biology & Disease |
| School | Keck School of Medicine |
| Date defended/completed | 2011-03-11 |
| Date submitted | 2011 |
| Restricted until | Restricted until 03 Nov. 2012. |
| Date published | 2012-11-03 |
| Advisor (committee chair) |
Taylor, Clive R. Epstein, Alan L. |
| Advisor (committee member) |
Kaslow, Harvey McMillan, Minnie Horwitz, David McDonough, Alicia |
| Abstract | Tumor immune tolerance can derive from the recruitment of suppressor cell populations, including myeloid-derived suppressor cells (MDSC). MDSCs inhibit anti-tumor T cell responses through a variety of mechanisms including nutrient depletion, production of reactive oxygen and nitrogen species, VEGF expression, and regulatory T cell expansion. In cancer patients and murine tumor models, MDSC accumulation correlates with increased stage and tumor burden, but the frequency and mechanisms of MDSC induction in human cancer remain poorly understood. This study examined the ability of a diverse set of human solid tumor cell lines to induce MDSC using in vitro tumor co-culture methods. Newly induced suppressor cells were characterized for morphology, phenotype, and gene expression. Of over 100 solid tumor cell lines examined, 45 generated canonical CD33+ HLADRlow Lineage- MDSC, with high frequency of induction by cervical, ovarian, colorectal, renal cell, and head and neck squamous cell carcinoma cell lines. CD33+ MDSC could be induced by some cancer cell lines of all tumor types examined with the notable exception of breast cancer cell lines (0/9, inclusive of models with different hormone and HER2 mutation status). Upon further examination, breast cancer cell lines and other tumor types with infrequent CD33+ MDSC induction preferentially induced an undiscovered CD11b+ CD33low HLADRlow Lineage- MDSC subset. Gene and protein expression, neutralization, and cytokine induction experiments determined that the ability of tumor cell lines to induce CD33+ MDSC depended upon over-expression of IL-1β, IL-6, TNFα, VEGF, and GM-CSF, while CD11b+ MDSCinduction correlated with over-expression of FLT3L and TGFβ. Both CD33+ and CD11b+ MDSC subsets appeared as immature myeloid cells by Wright-Giemsa staining and had significantly up-regulated expression of inducible nitric oxide synthase, TGFβ, NADPH oxidase, VEGF, and arginase-1 genes compared with normal myeloid cells.; Furthermore, increased expression of transcription factors HIF1α, STAT3, and C/EBPβ distinguished suppressive from non-suppressive tumor cell line-educated myeloid cells. Interestingly, CD33+ and CD11b+ subsets showed differential expression of these transcription factors and therapeutic reversal of suppressive function coincided with decreasing STAT3 and HIF1α in CD33+ cells but with decreasing C/EBPβ in CD11b+ MDSC. These studies demonstrate the universal nature of MDSC induction by human cancers and characterize two distinct populations of MDSC recognized by CD33+ HLADRlow HIF1α+/STAT3+ and CD11b+ HLADRlow C/EBPβ+ biomarkers. The unraveling of these different subsets in human cancers should enable the development of novel diagnostic and therapeutic reagents for cancer immunotherapy. |
| Keyword | immunology; cancer; immunotherapy; tumor immunity; myeloid-derived suppressor cells; cytokines; hypoxia-inducible factor 1 alpha; tumor cell lines; human; caat-enhancer-binding protein beta; signal transducer and activator of transcription 3; interleukin-6; interleukin-1 beta; granulocyte macrophage-colony stimulating factor; vascular endothelial growth factor; tumor necrosis factor alpha; Fms-related tyrosine kinase 3 ligand; transforming growth factor beta |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m3872 |
| Rights | Lechner, Melissa Genevieve |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Lechner-4434 |
| Archival file | uscthesesreloadpub_Volume62/etd-Lechner-4434.pdf |
Description
| Title | Page 1 |
| Full text | HUMAN MYELOID-DERIVED SUPPRESSOR CELLS IN CANCER: INDUCTION, FUNCTIONAL CHARACTERIZATION, AND THERAPY by Melissa Genevieve Lechner A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (SYSTEMS BIOLOGY AND DISEASE) May 2011 Copyright 2011 Melissa Genevieve Lechner |
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