Interleukin-10 attenuates tumour growth by inhibiting interleukin-6/signal transducer and activator of transcription 3 signalling in myeloid-derived suppressor cells

Bo-Ra Lee; Bo-Eun Kwon; Eun-Hye Hong; Aeri Shim; Jae-Hyoung Song; Hong-Min Kim; Sun-Young Chang; Yeon-Jeong Kim; Mi-Na Kweon; Je-In Youn; Hyun-Jeong Ko

doi:10.1016/j.canlet.2016.07.012

Interleukin-10 attenuates tumour growth by inhibiting interleukin-6/signal transducer and activator of transcription 3 signalling in myeloid-derived suppressor cells

Cancer Lett. 2016 Oct 10;381(1):156-64. doi: 10.1016/j.canlet.2016.07.012. Epub 2016 Jul 16.

Authors

Affiliations

¹ Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea.
² Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, South Korea.
³ College of Pharmacy, Ajou University, Suwon 16499, South Korea.
⁴ College of Pharmacy, Inje University, Gimhae 50834, South Korea.
⁵ Mucosal Immunology Lab., Department of Convergence Medicine, University of Ulsan College of Medicine/Asan Medical Center, Seoul 05505, South Korea.
⁶ Wide River Institute of Immunology, Seoul National University College of Medicine, Hongcheon 25159, South Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080 South Korea.
⁷ Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea. Electronic address: hjko@kangwon.ac.kr.

PMID: 27431309
DOI: 10.1016/j.canlet.2016.07.012

Abstract

Interleukin-10 (IL-10) is a well-characterized anti-inflammatory cytokine, but its role in anti-cancer immunity is controversial. After injection with TC-1 cancer cells, we observed more rapid tumour growth and significantly higher interleukin-6 (IL-6) production in IL-10 knockout (IL-10(-/-)) mice than wild-type (WT) mice. Blocking IL-6 with an anti-IL-6 receptor (IL-6R) monoclonal antibody (mAb) inhibited tumour growth and myeloid-derived suppressor cell (MDSC) generation, which were significantly increased in IL-10-deficient mice. MDSCs and tumour cells from IL-10(-/-) mice had increased phosphorylated signal transducer and activator of transcription 3 (p-STAT3) levels. Treatment with a STAT3 inhibitor, S3I, reduced tumour growth, inhibited MDSC expansion, reduced IL-6 in tumours, and relieved T cell suppression. The combination of anti-IL-6R mAb and S3I further inhibited tumour growth compared to S3I treatment alone. These results suggested that the inhibition of the IL-6/STAT3 signalling axis is a candidate anti-cancer strategy, especially under systemic inflammatory conditions with high IL-6.

Keywords: Cancer; Interleukin-10; Interleukin-6; Myeloid-derived suppressor cells; Signal transducer and activator of transcription 3.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Monoclonal / pharmacology
Antineoplastic Combined Chemotherapy Protocols / pharmacology
Cell Line, Tumor
Cell Proliferation* / drug effects
Female
Genotype
Interleukin-10 / deficiency
Interleukin-10 / genetics
Interleukin-10 / metabolism*
Interleukin-6 / metabolism*
Mice, Inbred C57BL
Mice, Knockout
Myeloid-Derived Suppressor Cells / metabolism*
Myeloid-Derived Suppressor Cells / pathology
Phenotype
Phosphorylation
Receptors, Interleukin-6 / antagonists & inhibitors
Receptors, Interleukin-6 / metabolism
STAT3 Transcription Factor / antagonists & inhibitors
STAT3 Transcription Factor / metabolism*
Signal Transduction* / drug effects
T-Lymphocytes / immunology
T-Lymphocytes / metabolism
Time Factors
Tumor Burden
Tumor Escape
Uterine Cervical Neoplasms / drug therapy
Uterine Cervical Neoplasms / genetics
Uterine Cervical Neoplasms / metabolism*
Uterine Cervical Neoplasms / pathology

Substances

Antibodies, Monoclonal
IL10 protein, mouse
Interleukin-6
Receptors, Interleukin-6
STAT3 Transcription Factor
Stat3 protein, mouse
interleukin-6, mouse
Interleukin-10