title: Immunity to murine prostatic tumors: continuous provision of T-cell help prevents CD8 T-cell tolerance and activates tumor-infiltrating dendritic cells.
abstract: We reported previously that tumor-specific CD8(+) T cells (TcR-I) become tolerant in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. In this study, we show that CD4(+) TcR transgenic (TcR-II) T cells transferred into TRAMP mice became activated in lymph nodes, trafficked to the prostate, and initially functioned as T(H)1 cells. Although a single cotransfer of TcR-II cells delayed TcR-I cell tolerization, repeated transfer of TcR-II cells was required to prevent TcR-I cell tolerization and significantly slowed progression of TRAMP prostate tumors. After transfer of TcR-II cells, dendritic cells within the tumor expressed higher levels of costimulatory molecules and displayed an enhanced ability to stimulate proliferation of naive T cells. Blockade of CD40-CD40L interactions during TcR-II transfer resulted in a profound reduction in dendritic cell stimulatory capacity and a partial loss of TcR-I effector functions and tumor immunity. These data show that sustained provision of activated tumor-specific CD4(+) T cells alters the immunosuppressive tumor microenvironment, ultimately leading to the control of tumor growth. These findings will assist in the design of more effective immunotherapeutic approaches for cancer.
authors.affiliation: Tumor Immunity and Tolerance Section, Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, SAIC-Frederick, Inc, Frederick, Maryland, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Shafer-Weaver
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Watkins
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Anderson
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Draper
authors.forename: Anatoli
authors.initials: A
authors.lastname: Malyguine
authors.forename: W Gregory
authors.initials: WG
authors.lastname: Alvord
authors.forename: Norman M
authors.initials: NM
authors.lastname: Greenberg
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Hurwitz
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000628:therapy; D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000037:antagonists & inhibitors / Q000276:immunology; D023201:CD40 Ligand / Q000037:antagonists & inhibitors / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D007108:Immune Tolerance; D016219:Immunotherapy, Adoptive; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000628:therapy
chemical_list: D019013:CD40 Antigens; D023201:CD40 Ligand