title: Trafficking of high avidity HER-2/neu-specific T cells into HER-2/neu-expressing tumors after depletion of effector/memory-like regulatory T cells.
abstract: BACKGROUND
  Cancer vaccines are designed to activate and enhance cancer-antigen-targeted T cells that are suppressed through multiple mechanisms of immune tolerance in cancer-bearing hosts. T regulatory cell (Treg) suppression of tumor-specific T cells is one barrier to effective immunization. A second mechanism is the deletion of high avidity tumor-specific T cells, which leaves a less effective low avidity tumor specific T cell repertoire available for activation by vaccines. Treg depleting agents including low dose cyclophosphamide (Cy) and antibodies that deplete CD25-expressing Tregs have been used with limited success to enhance the potency of tumor-specific vaccines. In addition, few studies have evaluated mechanisms that activate low avidity cancer antigen-specific T cells. Therefore, we developed high and low avidity HER-2/neu-specific TCR transgenic mouse colonies specific for the same HER-2/neu epitope to define the tolerance mechanisms that specifically affect high versus low avidity tumor-specific T cells.
  
  
  RESULTS
  High and low avidity CD8(+) T cell receptor (TCR) transgenic mice specific for the breast cancer antigen HER-2/neu (neu) were developed to provide a purified source of naïve, tumor-specific T cells that can be used to study tolerance mechanisms. Adoptive transfer studies into tolerant FVB/N-derived HER-2/neu transgenic (neu-N) mice demonstrated that high avidity, but not low avidity, neu-specific T cells are inhibited by Tregs as the dominant tolerizing mechanism. High avidity T cells persisted, produced IFNγ, trafficked into tumors, and lysed tumors after adoptive transfer into mice treated with a neu-specific vaccine and low dose Cy to deplete Tregs. Analysis of Treg subsets revealed a Cy-sensitive CD4(+)Foxp3(+)CD25(low) tumor-seeking migratory phenotype, characteristic of effector/memory Tregs, and capable of high avidity T cell suppression.
  
  
  CONCLUSIONS
  Depletion of CD25(low) Tregs allows activation of tumor-clearing high avidity T cells. Thus, the development of agents that specifically deplete Treg subsets should translate into more effective immunotherapies while avoiding autoimmunity.
authors.affiliation: The Sidney Kimmel Cancer Center at Johns Hopkins, John Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Vivian L
authors.initials: VL
authors.lastname: Weiss
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Lee
authors.forename: Hong
authors.initials: H
authors.lastname: Song
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Kouo
authors.forename: Chelsea M
authors.initials: CM
authors.lastname: Black
authors.forename: George
authors.initials: G
authors.lastname: Sgouros
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Jaffee
authors.forename: Todd D
authors.initials: TD
authors.lastname: Armstrong
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines; D002465:Cell Movement / Q000276:immunology*; D007156:Immunologic Memory; D008325:Mammary Neoplasms, Experimental / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D037182:T-Cell Antigen Receptor Specificity; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018719:Erb-b2 Receptor Tyrosine Kinases; C524056:Erbb2 protein, mouse