Cancer Immunology, Immunotherapy

, Volume 67, Issue 2, pp 271–283 | Cite as

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

  • Na Li
  • Jianing Wang
  • Na Zhang
  • Mengwei Zhuang
  • Zhaoyun Zong
  • Jiahuan Zou
  • Guosheng Li
  • Xiaoyan Wang
  • Huaiyu Zhou
  • Lining Zhang
  • Yongyu ShiEmail author
Original Article


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.


Hepatocellular carcinomas B7-H1 PD-L1 TNF-α Adaptive immune resistance 



B7-homologue 1


Hepatocellular carcinomas


IFN-γ receptor


Interferon regulatory factor


Quantitative PCR


Reverse transcription PCR


siRNA of negative control


Small interfering RNA


Author 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.

Compliance with ethical standards


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).

Supplementary material

262_2017_2086_MOESM1_ESM.pdf (1004 kb)
Supplementary material 1 (PDF 1004 kb)


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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Department of Immunology and Key Laboratory of Infection and Immunity of Shandong ProvinceShandong University School of Basic Medical SciencesJinanChina
  2. 2.Yinan People’s HospitalYinanChina
  3. 3.Department of HematologyQilu Hospital of Shandong UniversityJinanChina
  4. 4.Department of Parasitology, School of MedicineShandong UniversityJinanChina

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