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Cited by 278Immunotherapy and Immune ResponsesCytokine Signaling Pathways and InteractionsCancer Immunotherapy and Biomarkers

Interleukin‐6/ STAT 3 signaling as a promising target to improve the efficacy of cancer immunotherapy

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Kitamura, Hidemitsu, Ohno, Yosuke, Toyoshima, Yujiro, Ohtake, Junya, Homma, Shigenori, Kawamura, Hideki, Takahashi, Norihiko, Taketomi, Akinobu·2017·Cancer Science
DOI 10.1111/cas.13332PMC PMC5623748
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Abstract

Overcoming the immunosuppressive state in tumor microenvironments is a critical issue for improving the efficacy of cancer immunotherapy. Interleukin ( IL )‐6, a pleiotropic cytokine, is highly produced in the tumor‐bearing host. Previous studies have indicated that IL ‐6 suppresses the antigen presentation ability of dendritic cells ( DC ) through activation of signal transducer and activator of transcription 3 ( STAT 3). Thus, we focused on the precise effect of the IL ‐6/ STAT 3 signaling cascade on human DC and the subsequent induction of antitumor T cell immune responses. Tumor‐infiltrating CD 11b + CD 11c + cells isolated from colorectal cancer tissues showed strong induction of the IL ‐6 gene, downregulated surface expression of human leukocyte antigen ( HLA )‐ DR , and an attenuated T cell‐stimulating ability compared with those from peripheral blood mononuclear cells, suggesting that the tumor microenvironment suppresses antitumor effector cells. In vitro experiments revealed that IL ‐6‐mediated STAT 3 activation reduced surface expression of HLA ‐ DR on CD 14 + monocyte‐derived DC . Moreover, we confirmed that cyclooxygenase 2, lysosome protease and arginase activities were involved in the IL ‐6‐mediated downregulation of the surface expression levels of HLA class II on human DC . These findings suggest that IL ‐6‐mediated STAT 3 activation in the tumor microenvironment inhibits functional maturation of DC to activate effector T cells, blocking introduction of antitumor immunity in cancers. Therefore, we propose in this review that blockade of the IL ‐6/ STAT 3 signaling pathway and target molecules in DC may be a promising strategy to improve the efficacy of immunotherapies for cancer patients.

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  • IL6 activates the Janus kinase (JAK)/STAT3 pathway through binding to the IL6 receptor.

    “IL6 activates the Janus kinase (JAK)/Signal transducer and activator of transcription-3 (STAT3) pathway through binding to the IL6 receptor [81] (Figure 8).”

    From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [81]

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Cited by

Sorted by citations

Authors
Kitamura, H., Ohno, Y., Toyoshima, Y., Ohtake, J., Homma, S., Kawamura, H., Takahashi, N., & Taketomi, A.
Affiliations
Hokkaido University (JP)
Corresponding author
Kitamura, Hidemitsu
ORCID
Venue
Cancer Science
Publisher
Wiley
Published
2017-08-23
Volume
108
Issue
10
Pages
1947-1952
ISSN
  • 1347-9032 (ISSN-L)
  • 1349-7006
DOI
10.1111/cas.13332
PMC
PMC5623748
OpenAlex
W2740637641
Cited by
278
References
7
Citations by year
2026: 22 · 2025: 21 · 2024: 37 · 2023: 35 · 2022: 45 · 2021: 39 · 2020: 30 · 2019: 27 · 2018: 18 · 2017: 3
FWCI
2.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Science (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc)
  • Hokkaido University Collection of Scholarly and Academic Papers (Hokkaido University) (submittedVersion, cc-by-nc)
Funders
  • Japan Society for the Promotion of Science (25460584, 16K10526)
  • Ministry of Education, Culture, Sports, Science and Technology
  • Japan Agency for Medical Research and Development
  • Hokkaido University
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
interleukin-6, STAT3 signaling, dendritic cells, tumor microenvironment, immunosuppression, dendritic cell maturation, colorectal cancer, cyclooxygenase-2, arginase, lysosomal proteases, monocyte-derived dendritic cells, antitumor T-cell responses, cancer immunotherapy
MeSH terms
Animals, Antineoplastic Agents, Dendritic Cells, HLA-DR Antigens, Humans, Immunotherapy, Neoplasms, Signal Transduction, Interleukin-6, Gene Expression Regulation, Neoplastic, STAT3 Transcription Factor, Cyclooxygenase 2, Tumor Microenvironment

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