Identification and characterization of the immunodominant rat HER-2/neu MHC class I epitope presented by spontaneous mammary tumors from HER-2/neu-transgenic mice.
The HER-2/neu (neu-N)-transgenic mice are a clinically relevant model of breast cancer. They are derived from the parental FVB/N mouse strain and are transgenic for the rat form of the proto-oncogene HER-2/neu (neu). In this study, we report the identification of a MHC class I peptide in the neu protein that is recognized by CD8(+) T cells derived from vaccinated FVB/N mice. This 10-mer was recognized by all tumor-specific FVB/N T cells generated regardless of the TCR Vbeta region expressed by the T cell or the method of vaccination used, establishing it as the immunodominant MHC class I epitope in neu. T cells specific for this epitope were able to cure FVB/N mice of transplanted neu-expressing tumor cells, demonstrating that this is a naturally processed peptide. Altered peptide analogs of the epitope were analyzed for immunogenicity. Vaccination with dendritic cells pulsed with a heteroclitic peptide provided FVB/N and neu-N mice with increased protection against tumor challenge as compared with mice immunized with dendritic cells loaded with either wild-type or irrelevant peptide. Discovery of this epitope allows for better characterization of the CD8(+) T cell responses in the neu-N mouse model in which neu-specific tolerance must be overcome to produce effective antitumor immunity.
Ercolini
Anne M
AM
Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins, Graduate Program in Immunology, The Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
Machiels
Jean-Pascal H
JP
Chen
Yi Cheng
YC
Slansky
Jill E
JE
Giedlen
Martin
M
Reilly
R Todd
RT
Jaffee
Elizabeth M
EM
D016475:3T3 Cells; D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D002461:Cell Line, Transformed; D002999:Clone Cells; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D018734:Genes, erbB-2 / Q000276:immunology*; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D064532:Histocompatibility Antigen H-2D; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism*; D007275:Injections, Intravenous; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D010449:Peptide Mapping; D000090063:Proto-Oncogene Mas; D051381:Rats; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D006131:Growth Inhibitors; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D016056:Immunodominant Epitopes; C000715470:MAS1 protein, human; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D019444:Vaccines, DNA