Evaluation of Immune Responses Mediated by Listeria-Stimulated Human Dendritic Cells: Implications for Cancer Vaccine Therapy
Abstract
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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2015
- Accession Number
- AD1008545
Entities
People
- David J. Chung
Organizations
- Sloan-Kettering Institute