Induction of Cytotoxic T Lymphocytes for Immunotherapy of Breast Cancer

摘要

Cytotoxic T lymphocytes (at) play an important role in eradicating tumor cells. The purpose of this project is to determine whether fusion peptides composed of insertion signal- sequences and peptides derived from the breast cancer antigen HER2/neu can improve antigen presentation and induce antitumor Cm with higher efficiency against breast cancer. We demonstrated that the addition of synthetic signal sequence at the NH2-terminus, but not at the COOH-terminus, of the HER2/neu epitopes greatly enhanced their presentation in antigen processing deficient cells, breast cancer cells and dendritic cells. Importantly, peptide constructs, composed of the HER2/neu epitopes replacing the hydrophobic part of the signal sequences were the most effective. The efficiency of the signal sequences in facilitating the HER2/neu peptide presentation was confirmed also by using IFN-g release assays. We also studied the mechanisms involved in the enhancement of antigen presentation by the fusion peptides, and proved that the effective presentation of the loaded peptide constructs is a result of their efficient loading into the cytosol and not simple binding to the surface HLA molecules. These findings may be of practical significance for the development of synthetic anticancer vaccines and in vtiro immunization of Cm for adoptive immunotherapy.