title: IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4(+) T cells.
abstract: Immunosuppression in tumor microenvironments critically affects the success of cancer immunotherapy. Here, we focused on the role of interleukin (IL)-6/signal transducer and activator of transcription (STAT3) signaling cascade in immune regulation by human dendritic cells (DCs). IL-6-conditioned monocyte-derived DCs (MoDCs) impaired the presenting ability of cancer-related antigens. Interferon (IFN)-γ production attenuated by CD4(+) T cells co-cultured with IL-6-conditioned MoDCs corresponded with decreased DC IL-12p70 production. Human leukocyte antigen (HLA)-DR and CD86 expression was significantly reduced in CD11b(+)CD11c(+) cells obtained from peripheral blood mononuclear cells (PBMCs) of healthy donors by IL-6 treatment and was STAT3 dependent. Arginase-1 (ARG1), lysosomal protease, cathepsin L (CTSL), and cyclooxygenase-2 (COX2) were involved in the reduction of surface HLA-DR expression. Gene expressions of ARG1, CTSL, COX2, and IL6 were higher in tumor-infiltrating CD11b(+)CD11c(+) cells compared with PBMCs isolated from colorectal cancer patients. Expression of surface HLA-DR and CD86 on CD11b(+)CD11c(+) cells was down-regulated, and T cell-stimulating ability was attenuated compared with PBMCs, suggesting that an immunosuppressive phenotype might be induced by IL-6, ARG1, CTSL, and COX2 in tumor sites of colorectal cancer patients. There was a relationship between HLA-DR expression levels in tumor tissues and the size of CD4(+) T and CD8(+) T cell compartments. Our findings indicate that IL-6 causes a dysfunction in human DCs that activates cancer antigen-specific Th cells, suggesting that blocking the IL-6/STAT3 signaling pathway might be a promising strategy to improve cancer immunotherapy.
authors.affiliation: Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815, Japan.|Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ohno
authors.affiliation: Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815, Japan. kitamura@igm.hokudai.ac.jp.
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Kitamura
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Ohtake
authors.affiliation: Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Kaneumi
authors.affiliation: Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Sumida
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan.
authors.forename: Shigenori
authors.initials: S
authors.lastname: Homma
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kawamura
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Minagawa
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Shibasaki
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Taketomi
mesh_terms: D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D001119:Arginase / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D018845:CD11 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005786:Gene Expression Regulation; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D051940:B7-2 Antigen; D018845:CD11 Antigens; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma; D051546:Cyclooxygenase 2; D001119:Arginase
keywords: Antigen presentation; Dendritic cells; HLA class II; Helper T cells; IL-12