Hepatic IRF8 expression suppresses hepatocellular carcinoma progression and enhances the response to anti-PD-1 therapy.

Therapeutic blockade of the programmed cell death protein-1 (PD-1) immune checkpoint pathways has resulted in significant reactivation of T-cell mediated antitumor immunity and is a promising clinical anticancer treatment modality in several tumor types, but the durable response rate remains relatively low (15-20%) in most hepatocellular carcinoma (HCC) patients for unknown reasons. Evidences reveal that the interferon signaling pathway plays a critical role in modulating the efficacy and sensitivity of anti-PD-1 therapy against multiple tumor types, but the mechanisms are unclear. Using Kaplan-Meier survival analysis based on HCC databases, we found that deceased expression of interferon regulatory factor (IRF8) in HCC, among all the nine IRF members which regulate interferon signals, was associated with the poor prognosis of HCC patients. Moreover, gene set enrichment analysis identified the IFN-gama and PD-1 signaling signatures as the top suppressed pathways in IRF8 low HCC patients. Contrarily, overexpression of IRF8 in HCC cells significantly enhanced antitumor effects in immune-competent mice, modulating infiltration of tumor associated macrophages (TAMs) and T cells exhaustion in tumor microenvironment. We further demonstrated that IRF8 regulated recruitment of TAMs by inhibiting the expression of CCL20. Mechanically, IRF8-mediated repression of c-fos transcription resulted in decreased expression of CCL20, rather than directly bound to CCL20 promoter region. Importantly, adeno-associated virus 8-mediated hepatic IRF8 rescue significantly suppressed HCC progression and enhanced the response to anti-PD-1 therapy. In conclusion: This work identified IRF8 as an important prognostic biomarker in HCC patients which predicted the response and sensitivity to anti-PD-1 therapy and uncovered it as a new therapeutic target for enhancing the efficacy of immune therapy.