The subject of this study is the human immune response to a tumor antigen mucin (MUC-1) that was identified as T-cell target antigen shared among solid tumors of epithelial cell origin. The emphasis of the work proposed for the continuation of this grant will be on approaches that may increase the immunogenicity of this molecule and suggest appropriate immunogens and delivery systems that may be applied in constructing MUC-1-based cancer vaccines and other forms of MUC-1-based immunotherapy. The investigators will test the hypothesis that MUC-1 could serve as a tumor rejection antigen if appropriately presented to the immune system (Specific Aim 1), or appropriately targeted by effector T-cells (Specific Aim 2). Most of the work will be performed in vitro with human cells. Several questions will be asked in vivo in mouse models specifically evaluated for that purpose.
The aims are the following:
Specific Aim 1. Present MUC-1 on dendritic cells (DC) and compare T-cell responses generated from healthy individuals to those found in cancer patients or derived by stimulation with MUC-1 presented on tumor cells. The investigators will ask: 1) Do DC-primed MUC-1 specific T-cells from healthy individuals differ from MUC-1-specific T-cells derived from cancer patients by stimulation with tumor cells? and 2) Do DC-printed MUC-1-specific T-cell from cancer patients differ from DC-primed T-cells derived from healthy individuals? In vivo correlates to the in vitro experiments will be performed in two mouse strains, C57BL/6 and C57BL/6-MUC-1 transgenic.
Specific Aim 2. Use cloned MHC-unrestricted MUC-1 specific T-cell receptors (TCR) for structural and functional analyses and evaluate for immunotherapy. The investigators will test a hypothesis that the MUC-1-specific TCR can be a universal reagent for adoptive immunotherapy of every patient's MUC-1-expressing tumor. The MUC-1 specific function of a cloned TCR will be confirmed in test systems in vitro and then transduced into human and mouse T-cells or hematopoietic stem cells. In vivo correlates to these experiments will be performed in C57BL/6 and C57BL/6-MUC-1 transgenic mice.
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