Show simple item record

dc.contributor.advisorXiang, Jimen_US
dc.creatorChan, Timen_US
dc.date.accessioned2006-08-23T20:37:17Zen_US
dc.date.accessioned2013-01-04T04:54:05Z
dc.date.available2006-08-28T08:00:00Zen_US
dc.date.available2013-01-04T04:54:05Z
dc.date.created2006-08en_US
dc.date.issued2006-08-17en_US
dc.date.submittedAugust 2006en_US
dc.identifier.urihttp://hdl.handle.net/10388/etd-08232006-203717en_US
dc.description.abstractHuman Epidermal Growth Factor Receptor 2 (HER-2/neu) is a breast tumor antigen (Ag) commonly overexpressed in 30% of breast cancer cases. Both HER-2/neu-targeted DNA-based and transgene modified dendritic cell (DC)-based vaccines are potent elements in eliciting HER-2/neu specific antitumor immune responses; however, there has been no side-by-side comparison of these two different immunization methods. We utilized an in vivo murine tumor model expressing the rat neu Ag to compare the immunization efficacy between DC transduced with replication-deficient adenovirus containing neu (AdVneu), to form DCneu, and plasmid DNA (pcDNA) vaccine. DCneu displayed an upregulation of immunologically important molecules and inflammatory cytokines expression such as IL-6 that partially mediated conversion of the regulatory T (Tr) cell suppression. Wildtype FVB/N mice immunized with DCneu induced stronger HER-2/neu-specific humoral and cellular immune responses compared to plasmid DNA immunized mice. Furthermore, mice immunized with DCneu remained completely protected from tumor challenge compared to partial or no protection observed in DNA immunized mice in two tumor animal models. In FVBneuN transgenic mice, which develop spontaneous breast tumors at 4-8 months of age, DCneu significantly delayed tumor onset when immunization conducted in mice at a younger age. Taken together, we demonstrated that a HER-2/neu-gene modified DC vaccine is more potent than a plasmid DNA vaccine in inducing neu specific immune responses resulting in greater protective and preventative effects in the tumor models examined. In another study, we examined the use of a DC-based cancer vaccine involving the phagocytosis of apoptotic tumor cells expressing heat shock protein 70 (HSP70). The dual role of HSP70, as an antigenic peptide chaperone and danger signal, makes it especially important in DC-based vaccination. In this study, we investigated the impacts of apoptotic transgenic MCA/HSP tumor cells expressing HSP70 on DC maturation, T cell stimulation and overall vaccine efficacy. We found that DC with phagocytosis of MCA/HSP in the early phase of apoptosis expressed more peptide-major histocompatibility class (pMHC) I complexes, stimulated stronger cytotoxic T lymphocytes (CTL) responses and induced greater immune protection against MCA tumor cell challenge, compared to mice immunized with DC that phagocytosed MCA/HSP cells in the late phase of apoptosis. Taken together, our data demonstrated that HSP70 expression on apoptotic tumor cells stimulated DC maturation and DC with phagocytosis of apoptotic tumor cells expressing HSP70 in early phase of apoptosis more efficiently induced tumor-specific CTL responses and immunity than DC with phagocytosis of apoptotic tumor cells in late phase of apoptosis. Overall, we have examined variations in designing DC-based cancer vaccines in two completely different model systems. Taken together, our results may have an important impact in designing DC-based antitumor vaccines.en_US
dc.language.isoen_USen_US
dc.subjectreplication deficient adenovirusen_US
dc.subjectcancer vaccineen_US
dc.subjectbreast canceren_US
dc.subjectdendritic cellen_US
dc.subjectHER-2/neuen_US
dc.subjectapoptosisen_US
dc.subjectHeat Shock Protein 70en_US
dc.titleDendritic cell based cancer vaccines using adenovirally mediated expression of the HER-2/neu gene and apoptotic tumor cells expressing heat shock protein 70en_US
thesis.degree.departmentPathologyen_US
thesis.degree.disciplinePathologyen_US
thesis.degree.grantorUniversity of Saskatchewanen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophy (Ph.D.)en_US
dc.type.materialtexten_US
dc.type.genreThesisen_US
dc.contributor.committeeMemberSaxena, Anuragen_US
dc.contributor.committeeMemberSami, Ameren_US
dc.contributor.committeeMemberQureshi, Mabooden_US
dc.contributor.committeeMemberKrahn, Johnen_US
dc.contributor.committeeMemberBathe, Oliveren_US
dc.contributor.committeeMemberSharma, Rajendra K.en_US


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record