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MODULATION OF HUMAN TUMOR ANTIGEN-SPECIFIC T CELL RESPONSES BY PROGRAMMED DEATH-1 BLOCKADE
by
Raymond M. Wong
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR MICROBIOLOGY AND IMMUNOLOGY)
December 2006
Copyright 2006 Raymond M. Wong
Object Description
| Title | Modulation of human tumor antigen-specific T cell responses by programmed death-1 blockade |
| Author | Wong, Raymond M. |
| Author email | raymondw@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Microbiology & Immunology |
| School | Keck School of Medicine |
| Date defended/completed | 2006-09-27 |
| Date submitted | 2006 |
| Restricted until | Unrestricted |
| Date published | 2006-11-15 |
| Advisor (committee chair) | Weber, Jeffrey |
| Advisor (committee member) |
Epstein, Alan L. Tahara, Stanley M. Kast, W. Martin |
| Abstract | Negative costimulatory signaling mediated via cell surface Programmed Death-1 (PD-1) expression modulates T and B cell activation and is critical for maintaining peripheral tolerance. Abrogation of the PD-1 pathway may therefore be useful strategy to enhance the induction of antigen-specific T cells by vaccination. In these studies, we examined the effects of a fully human PD-1-abrogating antibody on the in vitro expansion and functional profile of human CD8+ T cells (CTLs) specific for the melanoma-associated antigens gp100 and MART-1. PD-1 blockade during peptide stimulation augmented the absolute numbers of CD3+, CD4+, CD8+, and MHC:peptide tetramer-binding CTLs. This correlated with increased frequencies of IFN-gamma-secreting antigen-specific cells and augmented lysis of peptide-pulsed targets as well as gp100+/MART+ melanoma cell lines. PD-1 blockade also increased the fraction of antigen-specific CTLs that recognized melanoma targets by degranulation, suggesting increased recognition efficiency for cognate peptide. The increased frequencies and absolute numbers of antigen-specific CTLs by PD-1 blockade resulted primarily from augmented proliferation, and not decreased apoptosis. Kinetic analysis of cytokine secretion demonstrated that PD-1 blockade increased both Type-1 and Type-2 cytokine secretion, without any apparent skewing of the cytokine repertoire. PD-1 blockade did not significantly alter the phenotype of peptide-stimulated gp100- and MART-1-specific CTLs, which were predominantly activated effector / effector memory cells characterized by a CD45RA(low), CD45RO(high), CCR7(low), CD62L(low), and CD44(high), expression profile. Vaccine-induced gp100- and MART-1-specific memory CTLs were also found to be dependent on CD4+ T help for optimal expansion during in vitro peptide stimulation. These findings suggest that PD-1 blockade may augment CTL expansion directly and/or indirectly through the augmented provision of CD4+ T help.; These findings contribute to the basic understanding of human CTL expansion and have implications for developing new cancer immunotherapy strategies. |
| Keyword | tumor antigen; costimulation; T cells; PD-1 |
| 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 |
| Type | texts |
| Legacy record ID | usctheses-m148 |
| Contributing entity | University of Southern California |
| Rights | Wong, Raymond M. |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@lib.usc.edu |
| Filename | etd-Wong-20061115 |
| Archival file | uscthesesreloadpub_Volume44/etd-Wong-20061115.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | MODULATION OF HUMAN TUMOR ANTIGEN-SPECIFIC T CELL RESPONSES BY PROGRAMMED DEATH-1 BLOCKADE by Raymond M. Wong A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (MOLECULAR MICROBIOLOGY AND IMMUNOLOGY) December 2006 Copyright 2006 Raymond M. Wong |
