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Activated hepatic stellate cells regulate MDSC migration through the SDF-1/CXCR4 axis in an orthotopic mouse model of hepatocellular carcinoma

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Abstract

Hepatic stellate cells (HSCs) are important stromal cells and pivotal mediators involved in the pathogenesis and immunosuppression of hepatocellular carcinoma (HCC). The liver has been demonstrated to be a site for accumulation of tumor-induced myeloid-derived suppressor cells (MDSCs). We previously reported that HSCs induced an increase in the number of MDSCs in HCC. However, how MDSCs are recruited in HCC remains largely unclear. In the present study, we found that HSC-conditioned medium (HSC-CM) induced bone marrow-derived cell and splenocyte migration, especially MDSC migration. Using chemokine-neutralizing antibodies and chemokine receptor inhibitors, we found that HSCs promoted MDSC migration through the SDF-1/CXCR4 axis. Subsequently, we used an orthotopic mouse liver tumor model to determine how HSCs mediated MDSC migration to HCC in vivo. The in vivo results indicated that pretreatment of MDSCs with a CXCR4 inhibitor or injection with SDF-1-knocked down HSCs inhibited MDSC migration to the spleen and liver of the tumor-bearing mice. Together, our findings indicate a central role for HSCs in MDSC migration mediated by the SDF-1/CXCR4 axis, thus revealing a potentially effective approach for modulating the tumor microenvironment by targeting HSCs in HCC.

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Abbreviations

C3:

Complement component 3

CCL/CCR:

CC chemokine ligand/chemokine receptor

CXCL/CXCR:

CXC chemokine ligand/chemokine receptor

DiR:

1,1′-Dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide

G-MDSCs:

Granulocytic myeloid-derived suppressor cells

HCC:

Hepatocellular carcinoma

HSC-CM:

HSC conditioned medium

HSCs:

Hepatic stellate cells

IL-1β:

Interleukin-1 beta

IL-8:

Interleukin-8

IVIS:

In vivo imaging system

MDSCs:

Myeloid-derived suppressor cells

Mo-MDSCs:

Monocytic myeloid-derived suppressor cells

PD-L1:

Programmed death ligand 1

RBC:

Red blood cells

SDF-1:

Stromal cell-derived factor 1

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Funding

This work was supported by grants from the National Nature Science Foundation of China (81602500 and 81572335); Outstanding Youth Science Research Personnel Training Plan of Fujian Province Colleges and Universities (2017); and Doctoral Start-up Foundation of Xiamen Medical College (K2016-07).

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Authors and Affiliations

  1. Key Laboratory of Functional and Clinical Translational Medicine, Department of Physiology, Xiamen Medical College, Xiamen, 361023, China

    Yaping Xu, Xiaohui Zheng, Liyue Huang & Xue Yi

  2. Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital, Xiamen University, Building 6, No. 209, South Hubin Road, Xiamen, 361004, China

    Fei Fang, Hui Jiao & Wenxiu Zhao

  3. Xiamen Key Laboratory of Respiratory Diseases, Xiamen, 361023, China

    Yaping Xu & Xue Yi

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  1. Yaping Xu
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Contributions

YX performed most of the experiments, analyzed the data, and wrote the manuscript. FF, HJ, XZ, LH, and XY assisted with and/or performed some of the experiments and revised the manuscript. WZ contributed to the design of the experiments and analysis and interpretation of the data, and revised the manuscript.

Corresponding author

Correspondence to Wenxiu Zhao.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All animal experimental protocols were performed in compliance with the Guidelines for the Institutional Animal Care and Use Committee of Xiamen University. (the date of animal research approval: 2015-02-26).

Animal source

BALB/c (H-2d, haplotype) mice aged 8–12 weeks were purchased from the National Rodent Laboratory Animal Resources, Shanghai, China.

Cell authentication

Not applicable because murine primary HSCs and MDSCs and murine HCC cell line H22 cells were used, which are lacking of short tandem repeat data. The H22 cells were purchased from Shanghai Cell Bank, Chinese Academy of Sciences.

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Xu, Y., Fang, F., Jiao, H. et al. Activated hepatic stellate cells regulate MDSC migration through the SDF-1/CXCR4 axis in an orthotopic mouse model of hepatocellular carcinoma. Cancer Immunol Immunother 68, 1959–1969 (2019). https://doi.org/10.1007/s00262-019-02414-9

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