title: Nondominant CD8 T cells are active players in the vaccine-induced antitumor immune response.
abstract: We previously reported that CD8(+) T cells are directed predominantly toward the immunodominant Her-2/neu (neu) epitope RNEU(420-429) in nontolerized FVB/N but not tolerized HER-2/neu (neu-N) mice. In this study, we screened overlapping peptides of the entire neu protein and identified six new epitopes recognized by vaccine-induced neu-N-derived T cells. Evaluation of individual nondominant responses by tetramer staining and IFN-γ secretion demonstrate that this repertoire is peripherally tolerized. To address the role that the complete CD8(+) T cell repertoire plays in vaccine-induced antitumor immunity, we created a whole-cell vaccine-expressing neu cDNA that has been mutated at the RNEU(420-429) anchor residue, thereby abrogating activation of immunodominant epitope responses. Studies comparing the mutated and nonmutated vaccines indicate that nondominant CD8(+) T cells can induce antitumor immunity when combined with regulatory T cell-depleting agents in both neu-N and FVB/N mice. Collectively, these studies demonstrate that the neu-directed T cell repertoire is not intrinsically incapable of eradicating tumors. Rather, they are suppressed by mechanisms of peripheral tolerance. Thus, these studies provide new insights into the function of the complete T cell repertoire directed toward a clinically relevant tumor Ag in tumor-bearing hosts.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Uram
authors.forename: Chelsea M
authors.initials: CM
authors.lastname: Black
authors.forename: Emilee
authors.initials: E
authors.lastname: Flynn
authors.forename: Lanqing
authors.initials: L
authors.lastname: Huang
authors.forename: Todd D
authors.initials: TD
authors.lastname: Armstrong
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Jaffee
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics; D016056:Immunodominant Epitopes / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D018719:Erb-b2 Receptor Tyrosine Kinases