title: Recruitment of latent pools of high-avidity CD8(+) T cells to the antitumor immune response.
abstract: A major barrier to successful antitumor vaccination is tolerance of high-avidity T cells specific to tumor antigens. In keeping with this notion, HER-2/neu (neu)-targeted vaccines, which raise strong CD8(+) T cell responses to a dominant peptide (RNEU(420-429)) in WT FVB/N mice and protect them from a neu-expressing tumor challenge, fail to do so in MMTV-neu (neu-N) transgenic mice. However, treatment of neu-N mice with vaccine and cyclophosphamide-containing chemotherapy resulted in tumor protection in a proportion of mice. This effect was specifically abrogated by the transfer of neu-N-derived CD4(+)CD25(+) T cells. RNEU(420-429)-specific CD8(+) T cells were identified only in neu-N mice given vaccine and cyclophosphamide chemotherapy which rejected tumor challenge. Tetramer-binding studies demonstrated that cyclophosphamide pretreatment allowed the activation of high-avidity RNEU(420-429)-specific CD8(+) T cells comparable to those generated from vaccinated FVB/N mice. Cyclophosphamide seemed to inhibit regulatory T (T reg) cells by selectively depleting the cycling population of CD4(+)CD25(+) T cells in neu-N mice. These findings demonstrate that neu-N mice possess latent pools of high-avidity neu-specific CD8(+) T cells that can be recruited to produce an effective antitumor response if T reg cells are blocked or removed by using approaches such as administration of cyclophosphamide before vaccination.
authors.affiliation: Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Ercolini
authors.forename: Brian H
authors.initials: BH
authors.lastname: Ladle
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Manning
authors.forename: Lukas W
authors.initials: LW
authors.lastname: Pfannenstiel
authors.forename: Todd D
authors.initials: TD
authors.lastname: Armstrong
authors.forename: Jean-Pascal H
authors.initials: JP
authors.lastname: Machiels
authors.forename: Joan G
authors.initials: JG
authors.lastname: Bieler
authors.forename: Leisha A
authors.initials: LA
authors.lastname: Emens
authors.forename: R Todd
authors.initials: RT
authors.lastname: Reilly
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Jaffee
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000235:genetics; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D003520:Cyclophosphamide / Q000008:administration & dosage; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D018734:Genes, erbB-2 / Q000276:immunology; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D015375:Receptors, Interleukin-2 / Q000276:immunology; D014611:Vaccination
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D003520:Cyclophosphamide