We have previously characterized the molecular chaperone function of a new stress protein, HSP110. We have shown that HSP110 is highly efficient in binding to substrate proteins, including tumor antigens such as HER-2/neu, by heat shock. The heat shock complex of HSP110 with the intracellular domain (ICD) of HER- 2/neu generated effective antigen-specific immune responses in a transgenic mouse model for human breast cancer. Although this immunity was capable of inhibition of the mammary tumors, complete eradication of the tumor requires an improvement in the HSP110-ICD vaccine formulation. Others (Reilly et al., 2001; Foy et al., 2002; Wolpoe et al., 2003) have reported that collaboration of both cellular and humoral HER-2/neu-targeted immune responses is required for eradication of mammary tumors. To achieve this goal, using the powerful immunoadjuvant activity of HSP110, we propose to design and evaluate a combinational vaccine of ICD plus BCD (extracellualr domain of HER-2/neu) in a chaperone complex with HSP110. We predict that generation of a strong cellular (by HSP110-ICD) and humoral (by HSP110-ECD) HER-2/neu-targeted immune responses may prevent and/or eradicate neu-overexpressing mammary tumors in a FVB-neu transgenic mouse model of human breast cancer. This hypothesis will be evaluated in Aim 1. In addition, the presence of CD4+ CD25+ regulatory T cells in breast cancer patients and FVB-neu transgenic mice may contribute to the progression of mammary tumors and failure of immunotherapy. We have recently shown that tumor-bearing animals reveal elevated CD4+ CD25+ regulatory T cells (Manjili et al., 2003). Therefore, in Aim 2, we will determine immunosuppressive function of regulatory T cells, and design and evaluate strategies, including this combinational HSP110 vaccine approach, to overcome the immunosuppressive function of regulatory T cells. The characterization of this HSP110-HER-2/neu vaccine can be expected to define new strategies for HER-2/neu-based immunotherapy of breast cancer and to have important clinical application.
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