Novel breast-tumor-associated MUC1-derived peptides: Characterization in D(b-)/^- x β2 microglobulin (β2m) null mice transgenic for a chimeric HLA- A2.1/D(b)-β2 microglobulin single chain

The MUC1 protein was found to be up-regulated in a spectrum of malignant tumors. T-cell responses to the MUC1 extracellular tandem repeat array (TRA) were observed in murine models as well as in breast-carcinoma patients. In the present study, we evaluated the anti-tumor potential of HLA-A2.1 -motif- selected peptides from non-TRA domains of the molecule. Peptide immunogenicity was examined in the D(b-)/^- X β2 microglobulin (β2m) null mice transgenic for a modified HLA-A2.1/D(b)-β2 microglobulin single chain (HHD mice). Our results show the existence of 3 novel HLA-A2.1-restricted MUC1-derived cytotoxic T-lymphocyte (CTL) epitopes. These peptides are processed and presented by the HHD-transfected breast-tumor cell line MDA-MB- 157. Moreover, CTL induced by these 3 peptides show higher lysis of target cells pulsed with breast-carcinoma-derived peptides than of targets pulsed with normal breast-tissue-derived peptides. These data suggest an important role for non-TRA MUC1-derived peptides as inducers of a MHC-restricted CTL reaction to a breast-carcinoma cell line and patient-derived tumor extracts.