Abstract

Immune checkpoint inhibitors (ICIs) have transformed systemic therapy for unresectable hepatocellular carcinoma (HCC). Nevertheless, their efficacy is limited to a small percentage of patients, leaving an opportunity for enhancement through synergistic combination therapies. We tested here the combined blockade of programmed death receptor 1 (PD-1) and CXCR4, a receptor for CXCL12 and a key mediator of immunosuppression in the tumor microenvironment in orthotopic grafted and autochthonous models of HCC. We evaluated tumor growth and survival outcomes and examined the underlying mechanisms using immunofluorescence, flow cytometry, RNA-sequencing, and transgenic mice experiments. Combined anti-CXCR4/PD-1 therapy had a robust impact on tumor growth and significantly prolonged survival in all murine preclinical models. The combination treatment successfully reprogrammed antigen-presenting cells, revealing the role of conventional type 1 dendritic cells (cDC1s) in the tumor microenvironment. Moreover, DC reprogramming enhanced anti-cancer immunity by facilitating CD8 T-cell accumulation and activation in the HCC tissue. The effectiveness of the anti-CXCR4 antibody/ICI combination treatment was compromised entirely in Batf3-KO mice deficient in cDC1 cells. Thus, combined ICI therapy with an anti-CXCR4 antibody has the potential to augment the anti-cancer effects and improve survival outcomes in HCC via reprogramming intra-tumoral cDC1 cells.