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

作　　者：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 

机构地区：[1]Department of General Surgery,Huashan Hospital,Cancer Metastasis Institute,Fudan University,12 Urumqi Road(M),Shanghai 200040,China [2]institutes of Biomedical Sciences,Fudan University,131 Dong An Road,Shanghai 200032,China

出　　处：《Cellular & Molecular Immunology》2022年第6期726-737,共12页中国免疫学杂志（英文版）

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

摘　　要：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-IFNαon 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-IFNαwas evaluated in both subcutaneous and orthotopic mouse models of HCC.Results The combination of Peg-IFNαwith 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-IFNαcould 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-IFNαcould 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-IFNαcan also generate a microenvironment favoring PD-1 blockade.Thus,the combination of Peg-IFNαand PD-1 blockade can be a promising strategy for HCC.

关 键 词：Hepatocellular carcinoma Tumor microenvironment PD-1 Pegylated interferon-α T-cell exhaustion 

分 类 号：R735.7[医药卫生—肿瘤]