Evaluation of Immune Responses Mediated by Listeria-Stimulated Human Dendritic Cells: Implications for Cancer Vaccine Therapy
Annual rept. 15 Jun 2013-14 Jun 2014
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 Listeria-activated DCs presenting a melanoma tumor-associated antigen. 3 Augment the immunogenicity of Listeria-activated DCs by inhibiting the immunosuppressive enzyme, indoleamine 2,3-dioxygenase. Key findings of the project include 1 Listeria infection, including that mediated by attenuated strains, induces moDC, DDC, and LC maturation and activation. 2 Listeria-treated DCs are functionally active, potent stimulators of T cell proliferation. 3 Listeria-treated moDCs are potent stimulators of autologous T cell proliferation. 4 Listeria treatment, as compared with standard inflammatory cytokine stimulation, does not promote the over-expression of inhibitory markers on DCs. 5 Listeria treatment, as compared with standard inflammatory cytokine stimulation, does not potentiate the expansion of immune-dampening regulatory T cells by moDCs. 6 WT and ActA-deficient Listeria induce IDO to much greater extent than LLO-deficient Listeria. 7 Listeria-treated moDCs, without exogenous cytokine supplementation, may be potent stimulators of antigen-specific CTLs. Studies of the mechanisms of Listeria-induced immunity and optimization of Listeria-based DC vaccines are ongoing.
- Medicine and Medical Research