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Evaluation of Immune Responses Mediated by Listeria-Stimulated Human Dendritic Cells: Implications for Cancer Vaccine Therapy
Annual rept. 15 Jun 2011-14 Jun 2012
SLOAN-KETTERING INST FOR CANCER RESEARCH NEW YORK
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The purpose of this project is to study the immunomodulatory effect of Listeria on human dendritic cells DCs to optimize Listeria-based DC cancer vaccines. The project aims are 1 Compare the activation and maturation of different human DC subsets in response to Listeria infection. 2 Define the induction of CD4CD8 T-cell and NK cell responses to Listeriaactivated DCs presenting a melanoma tumor-associated antigen. 3 Augment the immunogenicity of Listeria-activated DCs by inhibiting the immunosuppressive enzyme, indoleamine 2,3-dioxygenase. During the initial period of funding, critical parameters and baseline readouts of Listeria infection of monocyte-derived DCs moDCs were identified and validated. Key findings include 1 Listeria infection, including that mediated by attenuated strains, induces moDC maturation and activation. 2 Listeria-treated moDCs are functionally active as potent stimulators of T-cell proliferation. 3 Listeria treatment, as compared with standard inflammatory cytokine stimulation, does not promote the over-expression of inhibitory markers on moDCs. 4 Listeria treatment, as compared with standard inflammatory cytokine stimulation, does not potentiate the expansion of immune-dampening regulatory T-cells by moDCs. These findings confirm the immune-stimulatory properties of Listeria as a vaccine adjuvant. Studies of other DC subtypes are underway to identify the optimal DC for further study in Aims 23.
APPROVED FOR PUBLIC RELEASE