title: Inactivation of tumor-specific CD8⁺ CTLs by tumor-infiltrating tolerogenic dendritic cells.
abstract: Cancer immunosurveillance failure is largely attributed to the insufficient activation of tumor-specific class I major histocompatibility complex (MHC) molecule (MHC-I)-restricted CD8⁺ cytotoxic T lymphocytes (CTLs). DEC-205⁺ dendritic cells (DCs), having the ability to cross-present, can present captured tumor antigens on MHC-I alongside costimulatory molecules, inducing the priming and activation of tumor-specific CD8⁺ CTLs. It has been suggested that reduced levels of costimulatory molecules on DCs may be a cause of impaired CTL induction and that some tumors may induce the downregulation of costimulatory molecules on tolerogenic DCs. To examine such possibilities, we established two distinct types of murine hepatoma cell lines, named Hepa1-6-1 and Hepa1-6-2 (derived from Hepa1-6 cells), and confirmed that they display similar antigenicities, as well as identical surface expression of MHC-I. We found that Hepa1-6-1 had the ability to grow continuously after subcutaneous implantation into syngeneic C57BL/6 mice and did not prime CD8⁺ CTLs. In contrast, Hepa1-6-2 cells, which display reduced levels of adhesion molecules, such as Intercellular Adhesion Molecule 1 (ICAM-1), failed to grow in vivo and efficiently primed CTLs. Moreover, Hepa1-6-1-derived factors, such as transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF) and α-fetoprotein (AFP), converted CD11c(high) MHC-II(high) DEC-205⁺ DC subsets into tolerogenic cells, displaying downregulated costimulatory molecules and having impaired cross-presenting capacities. These immunosuppressive tolerogenic DCs appeared to inhibit the induction of tumor-specific CD8⁺ CTLs and suppress their cytotoxic functions within the tumor. Together, the findings presented here provide a new method of cancer immunotherapy using the selective suppression, depletion or alteration of immunosuppressive tolerogenic DCs within tumors.
authors.affiliation: 1] Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan [2] Third Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Harimoto
authors.forename: Masumi
authors.initials: M
authors.lastname: Shimizu
authors.forename: Yohko
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Nakatsuka
authors.forename: Ayako
authors.initials: A
authors.lastname: Wakabayashi
authors.forename: Choitsu
authors.initials: C
authors.lastname: Sakamoto
authors.forename: Hidemi
authors.initials: H
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology; D039521:CD11c Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006528:Carcinoma, Hepatocellular / Q000276:immunology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D045142:Cross-Priming; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D009368:Neoplasm Transplantation; D011956:Receptors, Cell Surface / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D047368:Tumor Burden; D019139:Tumor Escape; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D039521:CD11c Antigen; C093569:DEC-205 receptor; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D000509:alpha-Fetoproteins; D018799:Intercellular Adhesion Molecule-1
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