Title |
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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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Creator |
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Accessrights |
open access |
Rights |
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en
The final publication is available at Springer via http://dx.doi.org/10.1007/s00262-015-1791-4
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Subject |
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Other
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Dendritic cells
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Other
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Antigen presentation
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Other
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HLA class II
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Other
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IL-12
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Other
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Helper T cells
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NDC
490
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Description |
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Abstract
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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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Publisher |
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Springer
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Date |
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Language |
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Resource Type |
journal article |
Version Type |
AM |
Identifier |
HDL
http://hdl.handle.net/2115/64455
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Relation |
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isVersionOf
DOI
https://doi.org/10.1007/s00262-015-1791-4
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PMID
26759006
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Journal |
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Cancer immunology, immunotherapy
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Volume Number65
Issue Number2
Page Start193
Page End204
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File |
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Oaidate |
2023-07-26 |