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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

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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.

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Abbreviations

7AAD:

7-Amino-actinomycin D

ARG1:

Arginase-1

CFSE:

Carboxyfluorescein succinimidyl ester

COX2:

Cyclooxygenase-2

CTL:

Cytotoxic T lymphocyte

CTSL:

Cathepsin L

DC:

Dendritic cell

DMSO:

Dimethyl sulfoxide

ELISA:

Enzyme-linked immunosorbent assay

ERK:

Extracellular signal-related kinase

FACS:

Fluorescence-activated cell sorting

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GM-CSF:

Granulocyte macrophage colony-stimulating factor

gp130:

Glycoprotein 130

HLA:

Human leukocyte antigen

IHC:

Immunohistochemistry

IL-6R:

Interleukin-6 receptor

IL:

Interleukin

JAK:

Janus kinase

mAb:

Monoclonal antibody

MAPK:

Mitogen-activated protein kinase

MDSC:

Myeloid-derived suppressor cell

Median FI:

Median fluorescence intensity

MFI:

Mean fluorescence intensity

MHC:

Major histocompatibility complex

MoDC:

Monocyte-derived dendritic cell

nor-NOHA:

Nw-hydroxy-l-arginine

PBS:

Phosphate-buffered saline

PCR:

Polymerase chain reaction

PD-1:

Programmed cell death protein 1

PD-L1:

Programmed cell death ligand 1

PI3 K:

Phosphoinositide 3-kinase

SD:

Standard deviation

STAT3:

Signal transducer and activator of transcription 3

STEAP:

6-transmembrane epithelial antigen of prostate

TGF:

Transforming growth factor

Th:

Helper T

TIL:

Tumor-infiltrating lymphocyte

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Acknowledgments

We are grateful to Ms. Ai Nishiuchi for her technical and secretarial assistance. This work was partially supported by a Grant-in-Aid for Scientific Research (25460584 to Hidemitsu Kitamura), a Research Fellowship for Young Scientists (251464 to Kentaro Sumida), a Grant-in-Aid for Translational Research Network Program from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), a Health and Labour Sciences Research Grant (11103410 to Hidemitsu Kitamura) from the Ministry of Health, Labour, and Welfare (MHLW), Japan, and by the Joint Research Program of the Institute for Genetic Medicine, Hokkaido University.

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Authors and Affiliations

  1. Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815, Japan

    Yosuke Ohno, Hidemitsu Kitamura, Junya Ohtake, Shun Kaneumi & Kentaro Sumida

  2. Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan

    Yosuke Ohno, Norihiko Takahashi, Shigenori Homma, Hideki Kawamura, Nozomi Minagawa, Susumu Shibasaki & Akinobu Taketomi

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  1. Yosuke Ohno
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Correspondence to Hidemitsu Kitamura.

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Ohno, Y., Kitamura, H., Takahashi, N. et al. 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. Cancer Immunol Immunother 65, 193–204 (2016). https://doi.org/10.1007/s00262-015-1791-4

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