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

Authors :
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
Source :
Cell Mol Immunol
Publication Year :
2022
Publisher :
Springer Science and Business Media LLC, 2022.

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.

Details

ISSN :
20420226
Volume :
19
Database :
OpenAIRE
Journal :
Cellular & Molecular Immunology
Accession number :
edsair.doi.dedup.....a692980d3d05739270094c56d2575f92
Full Text :
https://doi.org/10.1038/s41423-022-00848-3