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Evaluation of Immune Responses Mediated by Listeria-Stimulated Human Dendritic Cells: Implications for Cancer Vaccine Therapy

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Technical Report,15 Jun 2011,14 Jun 2015

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Sloan-Kettering Institute for Cancer Research New York United States

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The purpose of this project is to study the immunomodulatory effect of Listeria monocytogenes Lm on human dendritic cells DCs to optimize Lm-based DC cancer vaccines. The project aims are 1 Compare the activation and maturation of different human DC subsets in response to Lm infection. 2 Define the induction of CD4 CD8 T-cell and NK cell responses to Lm-activated DCs presenting a melanoma tumor-associated antigen. 3 Augment the immunogenicity of Lm-activated DCs by inhibiting the immunosuppressive enzyme, indoleamine 2,3-dioxygenase. Key findings of the project include 1 Lm, including attenuated strains, induces human DC maturation and activation. 2 Lm induces less inhibitory receptor expression on mature DCs than standard inflammatory cytokine stimulation. 3 Lm-activated DCs are potent stimulators of allogeneic and autologous T cell proliferation. 4 Lm-conditioned DCs induce robust T cell activation that is associated with inhibitory receptor upregulation, providing rationale for the inclusion of checkpoint inhibition to augment T cell responses. 5 Lm treatment, despite vigorous T cell activation, does not potentiate DC-mediated expansion of immune-dampening regulatory T cells. 6 LLO-deficient Lm induces less IDO in DCs than WT and ActA-deficient strains. 7 Lm-treated moDCs, without exogenous cytokine supplementation, induce melanoma antigen-specific CTLs. Collectively, these findings confirm the immune-stimulatory properties of Lm, lend further support for Lm as a DC vaccine adjuvant to optimize vaccines efficacy, and identify immune checkpoint blockade as a rational complement to Lm-mediated immune activation.

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