PMID- 26759006
OWN - NLM
STAT- MEDLINE
DCOM- 20160606
LR  - 20240426
IS  - 1432-0851 (Electronic)
IS  - 0340-7004 (Print)
IS  - 0340-7004 (Linking)
VI  - 65
IP  - 2
DP  - 2016 Feb
TI  - 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.
PG  - 193-204
LID - 10.1007/s00262-015-1791-4 [doi]
AB  - 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)-gamma 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.
FAU - Ohno, Yosuke
AU  - Ohno Y
AD  - Division of Functional Immunology, Section of Disease Control, Institute for 
      Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 
      060-0815, Japan.
AD  - Department of Gastroenterological Surgery I, Hokkaido University Graduate School 
      of Medicine, Sapporo, 060-8638, Japan.
FAU - Kitamura, Hidemitsu
AU  - Kitamura H
AD  - 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.
FAU - Takahashi, Norihiko
AU  - Takahashi N
AD  - Department of Gastroenterological Surgery I, Hokkaido University Graduate School 
      of Medicine, Sapporo, 060-8638, Japan.
FAU - Ohtake, Junya
AU  - Ohtake J
AD  - Division of Functional Immunology, Section of Disease Control, Institute for 
      Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 
      060-0815, Japan.
FAU - Kaneumi, Shun
AU  - Kaneumi S
AD  - Division of Functional Immunology, Section of Disease Control, Institute for 
      Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 
      060-0815, Japan.
FAU - Sumida, Kentaro
AU  - Sumida K
AD  - Division of Functional Immunology, Section of Disease Control, Institute for 
      Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 
      060-0815, Japan.
FAU - Homma, Shigenori
AU  - Homma S
AD  - Department of Gastroenterological Surgery I, Hokkaido University Graduate School 
      of Medicine, Sapporo, 060-8638, Japan.
FAU - Kawamura, Hideki
AU  - Kawamura H
AD  - Department of Gastroenterological Surgery I, Hokkaido University Graduate School 
      of Medicine, Sapporo, 060-8638, Japan.
FAU - Minagawa, Nozomi
AU  - Minagawa N
AD  - Department of Gastroenterological Surgery I, Hokkaido University Graduate School 
      of Medicine, Sapporo, 060-8638, Japan.
FAU - Shibasaki, Susumu
AU  - Shibasaki S
AD  - Department of Gastroenterological Surgery I, Hokkaido University Graduate School 
      of Medicine, Sapporo, 060-8638, Japan.
FAU - Taketomi, Akinobu
AU  - Taketomi A
AD  - Department of Gastroenterological Surgery I, Hokkaido University Graduate School 
      of Medicine, Sapporo, 060-8638, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160112
PL  - Germany
TA  - Cancer Immunol Immunother
JT  - Cancer immunology, immunotherapy : CII
JID - 8605732
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (B7-2 Antigen)
RN  - 0 (CD11 Antigens)
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (HLA-DR Antigens)
RN  - 0 (Histocompatibility Antigens Class II)
RN  - 0 (Interleukin-6)
RN  - 0 (STAT3 Transcription Factor)
RN  - 187348-17-0 (Interleukin-12)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - EC 3.5.3.1 (Arginase)
SB  - IM
MH  - Antigen Presentation/immunology
MH  - Antigens, Neoplasm/immunology
MH  - Arginase/metabolism
MH  - B7-2 Antigen/metabolism
MH  - CD11 Antigens/metabolism
MH  - CD4-Positive T-Lymphocytes/*immunology/*metabolism
MH  - Cell Membrane/metabolism
MH  - Colorectal Neoplasms/genetics/immunology/metabolism
MH  - Cyclooxygenase 2/metabolism
MH  - Dendritic Cells/drug effects/*immunology/*metabolism
MH  - Epitopes, T-Lymphocyte/immunology
MH  - Gene Expression Regulation
MH  - HLA-DR Antigens/genetics/immunology/metabolism
MH  - Histocompatibility Antigens Class II/genetics/immunology/*metabolism
MH  - Humans
MH  - Interferon-gamma/biosynthesis
MH  - Interleukin-12/*biosynthesis
MH  - Interleukin-6/*metabolism/pharmacology
MH  - Lymphocyte Activation/immunology
MH  - Lymphocytes, Tumor-Infiltrating/immunology/metabolism
MH  - STAT3 Transcription Factor/metabolism
MH  - Signal Transduction
MH  - T-Cell Antigen Receptor Specificity/immunology
MH  - T-Lymphocyte Subsets/immunology/metabolism
PMC - PMC11028987
OTO - NOTNLM
OT  - Antigen presentation
OT  - Dendritic cells
OT  - HLA class II
OT  - Helper T cells
OT  - IL-12
COIS- All authors declare no conflict of interest.
EDAT- 2016/01/14 06:00
MHDA- 2016/06/09 06:00
PMCR- 2016/01/12
CRDT- 2016/01/14 06:00
PHST- 2014/11/17 00:00 [received]
PHST- 2015/12/29 00:00 [accepted]
PHST- 2016/01/14 06:00 [entrez]
PHST- 2016/01/14 06:00 [pubmed]
PHST- 2016/06/09 06:00 [medline]
PHST- 2016/01/12 00:00 [pmc-release]
AID - 10.1007/s00262-015-1791-4 [pii]
AID - 1791 [pii]
AID - 10.1007/s00262-015-1791-4 [doi]
PST - ppublish
SO  - Cancer Immunol Immunother. 2016 Feb;65(2):193-204. doi: 
      10.1007/s00262-015-1791-4. Epub 2016 Jan 12.