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

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-alpha (Peg-IFN alpha) with PD-1 blockade in HCC mouse models. METHODS: We analyzed the effects of Peg-IFN alpha 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 antiPD-1 and Peg-IFN alpha was evaluated in both subcutaneous and orthotopic mouse models of HCC. RESULTS: The combination of Peg-IFN alpha 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-IFN alpha 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 IFN alpha-IFNAR1-JAK1-STAT3 signaling pathway. The combination of PD-1 blockade with Peg-IFN alpha 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-IFN alpha can also generate a microenvironment favoring PD-1 blockade. Thus, the combination of Peg-IFN alpha and PD-1 blockade can be a promising strategy for HCC.