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The combination of PD-1 blockade with interferon-α has a synergistic effect on hepatocellular carcinoma

Cellular & Molecular Immunology volume 19, pages 726–737 (2022)Cite this article

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Abstract

Background

The efficacy of immune checkpoint inhibitors (ICIs), such as programmed cell death protein-1 (PD-1) or its ligand 1 (PD-L1) antibody, in hepatocellular carcinoma (HCC) is limited, and it is recommended that they be combined with other therapies. We evaluated the combination of pegylated interferon-α (Peg-IFNα) with PD-1 blockade in HCC mouse models.

Methods

We analyzed the effects of Peg-IFNα on tumor-infiltrating immune cells and PD-1 expression in the HCC immune microenvironment and examined the underlying mechanism of its unique effect on the PD-1 pathway. The in vivo efficacy of anti-PD-1 and Peg-IFNα was evaluated in both subcutaneous and orthotopic mouse models of HCC.

Results

The combination of Peg-IFNα with PD-1 blockade dramatically enhanced T-cell infiltration, improved the efficacy of PD-1 antibody and prolonged mouse survival compared with PD-1 antibody monotherapy. Mechanistically, Peg-IFNα could recruit cytotoxic CD8+ T cells to infiltrate the HCC microenvironment by inducing tumor cells to secrete the chemokine CCL4. Nevertheless, the HCC microenvironment quickly overcame the immune responses by upregulating PD-1 expression in CD8+ T cells via the IFNα-IFNAR1-JAK1-STAT3 signaling pathway. The combination of PD-1 blockade with Peg-IFNα could restore the cytotoxic capacity of CD8+ T cells and exerted a significant synergistic effect on HCC.

Conclusion

These results indicate that in addition to initiating the antitumor immune response itself, Peg-IFNα can also generate a microenvironment favoring PD-1 blockade. Thus, the combination of Peg-IFNα and PD-1 blockade can be a promising strategy for HCC.

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Data availability

All data generated or analyzed during this study are included in this published article and its additional files.

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Funding

This work was supported by the National Natural Science Foundation of China (81902390 and 81902952) and the National Key Research and Development Program of China (2017YFC1308604).

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Author notes

  1. These authors contributed equally: Ying Zhu, Mo Chen, Da Xu, Tian-En Li.

Authors and Affiliations

  1. Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China

    Ying Zhu, Mo Chen, Da Xu, Tian-En Li, Ze Zhang, Jian-Hua Li, Xiang-Yu Wang, Xin Yang, Lu Lu, Hu-Liang Jia, Qiong-Zhu Dong & Lun-Xiu Qin

  2. Institutes of Biomedical Sciences, Fudan University, 131 Dong An Road, Shanghai, 200032, China

    Qiong-Zhu Dong & Lun-Xiu Qin

Authors
  1. Ying Zhu
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Contributions

YZ, MC, DX, and T-EL designed and performed the experiments, analyzed the data, and wrote the paper; J-HL, X-YW, ZZ, and XY performed the experiments and analyzed the data; LL and H-LJ participated in the discussion and data interpretation; L-XQ, and Q-ZD designed and supervised the entire project, designed the experiments, analyzed the data, and wrote the paper.

Corresponding authors

Correspondence to Qiong-Zhu Dong or Lun-Xiu Qin.

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Competing interests

The authors declare no competing interests.

Ethics approval

The present study was performed in accordance with the Declaration of Helsinki. All experimental procedures involving animals were approved by the Animal Care and Use Committee of Fudan University. Approval for the use of human subjects was obtained from the research ethics committee of Huashan Hospital, Fudan University, and informed consent was obtained from each individual enrolled in this study.

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Zhu, Y., Chen, M., Xu, D. et al. The combination of PD-1 blockade with interferon-α has a synergistic effect on hepatocellular carcinoma. Cell Mol Immunol 19, 726–737 (2022). https://doi.org/10.1038/s41423-022-00848-3

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