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Fusobacterium nucleatum promotes M2 polarization of macrophages in the microenvironment of colorectal tumours via a TLR4-dependent mechanism

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Abstract

Fusobacterium nucleatum (Fn) has been shown to promote colorectal cancer (CRC) development by inhibiting host anti-tumour immunity. However, the impact of Fn infection on macrophage polarization and subsequent intestinal tumour formation as well as the underlying molecular pathways has not been investigated. We investigated the impact of Fn infection on macrophage polarization in human CRCs and cultured macrophages as well as the effects on macrophage phenotype and intestinal tumour formation in ApcMin/+ mice. We also examined whether macrophage-polarized activation challenged by Fn infection via a TLR4-dependent mechanism involved the IL-6/STAT3/c-MYC signalling cascade. Our data showed that macrophages are a major tumour-infiltrating immune cell type in human CRCs with Fn infection (P < 0.001). Fn infection increased M2 polarization of macrophages in vitro and in vivo, leading to intestinal tumour growth in ApcMin/+ mice. Moreover, Fn infection induced high expression of TLR4, IL-6, STAT3, p-STAT3, and c-MYC in cultured macrophages challenged with Fn, which was blocked by TAK-242 pre-treatment (P < 0.05). Interestingly, c-MYC protein was mainly co-localized with CD206+ M2 macrophages with Fn infection. In conclusion, we show that Fn infection increased M2 polarization of macrophages in vitro and in vivo. Furthermore, Fn infection enhanced colorectal tumour growth in a TLR4-dependent manner involving activation of the IL-6/p-STAT3/c-MYC signalling pathway. For the first time, our results indicate an immunosuppressive effect of Fn by promoting M2 polarization of macrophages through a TLR4-dependent mechanism, which may serve as a promising target for immunotherapy of Fn-related CRC.

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Abbreviations

CRC:

Colorectal cancer

E. coli :

Escherichia coli

FAB:

Fastidious anaerobe broth

FISH:

Fluorescence in situ hybridization

Fn :

Fusobacterium nucleatum

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

NE:

Neutrophil elastase

TAM:

Tumour associated macrophages

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Funding

This work was supported by the Youth Program of National Science Fund under Grant no. 81602163.

Author information

Author notes

  1. Ting Chen and Qing Li contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, The Affiliated Hospital of Chengdu University, Chengdu, 610081, China

    Ting Chen

  2. Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Sichuan, 646000, China

    Qing Li, Jiao Wu, Yaxin Wu, Wei Peng, Huan Li, Xiaowei Tang & Yan Peng

  3. Department of Pathology, The Affiliated Hospital of Southwest Medical University, Sichuan, 646000, China

    Jianmei Wang

  4. Department of Gastroenterology, The Affiliated Hospital of North Sichuan Medical College, Road Wenhua 63#, Region Shunqing, Nanchong, 637000, China

    Xiangsheng Fu

Authors
  1. Ting Chen
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  2. Qing Li
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Contributions

TC, QL, JW, YW, WP, and HL conducted the experiments. JW and XT analyzed the data. XF wrote the paper. YP and XF conceived and designed the study.

Corresponding author

Correspondence to Xiangsheng Fu.

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Conflict of interest

All authors declare no financial disclosures and no conflict of interest.

Ethical approval

The Ethical Committee on Animal Care and Animal Experiment of the Southwest Medical University gave approval to the use of mice for the animal research described in this paper (approval number: No. 201702004). The animals were maintained in accordance with the guidelines approved by this committee.

Animal source

All mice were purchased from the Nanjing Biomedical Research Institute of Nanjing University and maintained in specific pathogen-free conditions at the Animal Experimental Centre of Southwest Medical University.

Informed consent

Informed consent was obtained from all participants and the project was approved by the review board of Southwest Medical University (No. K2017027).

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Chen, T., Li, Q., Wu, J. et al. Fusobacterium nucleatum promotes M2 polarization of macrophages in the microenvironment of colorectal tumours via a TLR4-dependent mechanism. Cancer Immunol Immunother 67, 1635–1646 (2018). https://doi.org/10.1007/s00262-018-2233-x

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  • DOI: https://doi.org/10.1007/s00262-018-2233-x

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