Th1- and CTL driven cellular immunity is thought to be the most effective defense against chronic intracellular infections and cancer. We have recently demonstrated the existence of a novel Th1- and CTL-promoting mechanism, based on the ability of the appropriately-activated NK cells to induce type-1 polarized effector dendritic cells (DC1s). Based on our PRELIMINARY OBSERVATIONS that human NK cells can enhance the activation state of DCs and induce DC1s with elevated IL-12-producing ability, we intend to test the hypothesis that NK cell-dependent DC polarization will support the induction of Th1 cells and CTLs against tumor-related antigens. Furthermore, we hypothesize that DC1 induced in vitro by NK cells and their soluble products will act as superior inducers of tumor-specific responses in DC1-treated cancer patients in phase I/II clinical trials. This project will pursue four Specific Aims:
Specific Aim 1. Identify the requisite signals and characteristics of NK cells capable of inducing DC1 (DC1NK);
Specific Aim 2. Characterize NK-induced DC1NK, and identify the mechanisms of NK-dependent, DC1NK-mediated immunoregulation;
Specific Aim 3. Demonstrate that DC1NK are superior (to control DC matured by IL-lb/TNFa/IL-6/PGE2) inducers of melanoma- and colorectal cancer-specific Th1 cells and CTLs in human in vitro models;
Specific Aim 4. Demonstrate the feasibility and immunologic efficacy of DC1NK-based vaccines in phase I/II clinical trials (melanoma and colorectal cancer).
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