Novel breast-tumor-associated MUC1-derived peptides: characterization in Db-/- x beta2 microglobulin (beta2m) null mice transgenic for a chimeric HLA-A2.1/Db-beta2 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 Db-/- x beta2 microglobulin (beta2m) null mice transgenic for a modified HLA-A2.1/Db-beta2 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.
Carmon
L
L
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
El-Shami
K M
KM
Paz
A
A
Pascolo
S
S
Tzehoval
E
E
Tirosh
B
B
Koren
R
R
Feldman
M
M
Fridkin
M
M
Lemonnier
F A
FA
Eisenbach
L
L
D000818:Animals; D017951:Antigen Presentation; D001943:Breast Neoplasms / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D005260:Female; D005453:Fluorescence; D015972:Gene Expression Regulation, Neoplastic; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology; D015789:HLA-A2 Antigen / Q000276:immunology*; D064532:Histocompatibility Antigen H-2D; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018396:Mucin-1 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D010455:Peptides / Q000276:immunology; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D001613:beta 2-Microglobulin / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D015789:HLA-A2 Antigen; D064532:Histocompatibility Antigen H-2D; C116055:MUC1 tandem repeat peptide; D018396:Mucin-1; D010446:Peptide Fragments; D010455:Peptides; D011993:Recombinant Fusion Proteins; D001613:beta 2-Microglobulin