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Interferon Gamma-Induced Interferon Regulatory Factor 1 Activates Transcription of HHLA2 and Induces Immune Escape of Hepatocellular Carcinoma Cells

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Abstract—

Immunosuppression developed by cancer cells remains a leading cause of treating failure of immunotherapies. This study aimed to explore the function of human endogenous retrovirus-H long terminal repeat-associating 2 (HHLA2), an immune checkpoint molecule from the B7 family, in the immune escape in hepatocellular carcinoma (HCC). Mouse models with primary HCC or with xenograft tumors were established. The portion of tumor-associated macrophages (TAMs) and the level of PD-L1 in the tumor tissues were examined. THP-1 cells were treated with PMA to obtain a macrophage-like phenotype. The PMA-treated THP-1 cells were co-cultured with the HCC cells in Transwell chambers to examine the function of HHLA2 in chemotactic migration and polarization of macrophages. HHLA2 expression was correlated with infiltration of immune cells, especially macrophages, and was linked to poor prognosis of patients with HCC. HHLA2 knockdown reduced incidence rate of primary HCC in mice. It also reduced tumor metastasis, the portion of M2 macrophages, and the expression of PD-L1 in primary and xenograft tumors. In vitro, HHLA2 upregulation increased expression of PD-L1 in HCC cells indirectly by inducing M2 polarization and chemotactic migration of macrophages. Interferon gamma (IFNG) enhanced expression of interferon regulatory factor 1 (IFR1) in HCC cells, and IFR1 bound to the promoter region of HHLA2 to activate HHLA2 expression. This study suggested that the IFNG/IFR1/HHLA2 axis in HCC induces M2 polarization and chemotactic migration of macrophages, which leads to immune escape and development of HCC.

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Data Availability Statement

All the data generated or analyzed during this study are included in this published article.

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Acknowledgements

The authors would like to thank Natural Science Research Project of Anhui Educational Committee (No. KJ2020A0549), The First Affiliated Hospital of Bengbu Medical College Science Found for Distinguished Young Scholars (No. 2019byyfyjq03), and Research and Innovation Team of Bengbu Medical College (No. BYKC201908).

Funding

This work was supported by Natural Science Research Project of Anhui Educational Committee (No. KJ2020A0549), The First Affiliated Hospital of Bengbu Medical College Science Found for Distinguished Young Scholars (No. 2019byyfyjq03), and Research and Innovation Team of Bengbu Medical College (No. BYKC201908).

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Authors and Affiliations

  1. Department of Medical Oncology, First Affiliated Hospital of Bengbu Medical College, No. 287, Changhuai Road, Bengbu, 233004, Anhui, People’s Republic of China

    Rui Wang, Hui Guo, Xiaotong Tang, Tiantian Zhang, Yang Liu, Cheng Zhang, Hanbing Yu & Yumei Li

  2. Anhui Province Key Laboratory of Translational Cancer Research Affiliated to Bengbu Medical University, Bengbu, 233004, Anhui, People’s Republic of China

    Rui Wang, Hui Guo & Cheng Zhang

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Contributions

RW and HG are the guarantor of integrity of the entire study and contributed to the concepts; XTT and TTZ contributed to the design and definition of intellectual content of this study; and YL, CZ, HBY, and YML contributed to the experimental studies, data acquisition, and statistical analysis. All authors contributed to the manuscript preparation, read, and approved the final manuscript.

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Correspondence to Yumei Li.

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Ethical Approval

This study was ratified by the Ethical Committee of First Affiliated Hospital of Bengbu Medical College (Approval No.: BYYFY-2019KY035) and conducted according to the Declaration of Helsinki. Written informed consent was received from each respondent. Animal studies were approved by the Animal Ethics Committee of First Affiliated Hospital of Bengbu Medical College (BBMC-2018-JC00316). All animal procedures were conducted in line with the Guide for the Care and Use of Laboratory Animals (NIH, Bethesda, MD, USA).

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Rui Wang and Hui Guo contributed equally to this work.

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Wang, R., Guo, H., Tang, X. et al. Interferon Gamma-Induced Interferon Regulatory Factor 1 Activates Transcription of HHLA2 and Induces Immune Escape of Hepatocellular Carcinoma Cells. Inflammation 45, 308–330 (2022). https://doi.org/10.1007/s10753-021-01547-3

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