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Cross-talk between TNF-α and IFN-γ signaling in induction of B7-H1 expression in hepatocellular carcinoma cells

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Abstract

Clinical benefit from immunotherapy of B7-H1/PD-1 checkpoint blockade indicates that it is important to understand the regulatory mechanism of B7-H1 expression in cancer cells. As an adaptive response to the endogenous antitumor immunity, B7-H1 expression is up-regulated in HCC cells. B7-H1 expression is induced mainly by IFN-γ released from tumor-infiltrating T cells in HCC. In addition, HCC is a prototype of inflammation-related cancer and TNF-α is a critical component of inflammatory microenvironment of HCC. In the present study, we asked whether TNF-α can promote the expression of B7-H1 induced by IFN-γ in HCC cells. We found that JAK/STAT1/IRF1 was the primary pathway responsible for induction of B7-H1 expression by IFN-γ in human HCC cell lines. TNF-α and IFN-γ synergistically induced the expression of B7-H1 in the HCC cells. Moreover, the mechanism of the synergy was that TNF-α enhanced IFN-γ signaling by upregulating the expression of IFN-γ receptors. Furthermore, B7-H1 expression induced synergistically by TNF-α and IFN-γ in murine HCC cells facilitated tumor growth in vivo. Our findings suggest that TNF-α may enhance the adaptive immune resistance mediated by IFN-γ-induced B7-H1 in HCC cells.

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Abbreviations

B7-H1:

B7-homologue 1

HCC:

Hepatocellular carcinomas

IFNGR:

IFN-γ receptor

IRF:

Interferon regulatory factor

qPCR:

Quantitative PCR

RT-PCR:

Reverse transcription PCR

siNC:

siRNA of negative control

siRNA:

Small interfering RNA

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Authors and Affiliations

  1. Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44# Wenhua Xi Road, Jinan, 250012, China

    Na Li, Jianing Wang, Mengwei Zhuang, Zhaoyun Zong, Jiahuan Zou, Xiaoyan Wang, Lining Zhang & Yongyu Shi

  2. Yinan People’s Hospital, Yinan, China

    Na Zhang

  3. Department of Hematology, Qilu Hospital of Shandong University, Jinan, China

    Guosheng Li

  4. Department of Parasitology, School of Medicine, Shandong University, Jinan, China

    Huaiyu Zhou

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  1. Na Li
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  3. Na Zhang
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Contributions

YS designed and supervised the research. NL and ZZ executed the biochemical, cell biological experiments and the animal experiments. JW and NZ contributed reagents. GL and MZ performed the flow cytometry assay. JZ and XW contributed data collection. HZ and LZ contributed data analysis and interpretation. NL and YS prepared figures and wrote the paper.

Corresponding author

Correspondence to Yongyu Shi.

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Funding

This work was supported by the National Nature Science Foundation of China (Grant nos. 81372264 and 81672806); the Shandong Provincial Natural Science Foundation (Grant no. ZR2011HZ003).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval and ethical standards

Experiments involving animals were approved by the Animal Ethical and Welfare Committee of Shandong University School of Medicine with the permit number 201302072. All mouse experimental procedures were performed in accordance with the Regulations for the Administration of Affairs Concerning Experimental Animals approved by the State Council of People’s Republic of China.

Animal source

The Six-week-old female C57BL/6 mice were purchased from the Laboratory Animal Center of Shandong University (Jinan, China).

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Li, N., Wang, J., Zhang, N. et al. Cross-talk between TNF-α and IFN-γ signaling in induction of B7-H1 expression in hepatocellular carcinoma cells. Cancer Immunol Immunother 67, 271–283 (2018). https://doi.org/10.1007/s00262-017-2086-8

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