Combination therapy with dendritic cell vaccine and programmed death ligand 1 immune checkpoint inhibitor for hepatocellular carcinoma in an orthotopic mouse model

Abstract

Background: Hepatocellular carcinoma (HCC) is among the most common and lethal human cancers worldwide. Despite remarkable advances in treatment, high mortality in HCC patients remains a big challenge. To develop novel therapeutic strategies for HCC is thus urgently needed to improve patient survival. Dendritic cells (DC)-based vaccines can induce tumor-specific immunity and have emerged as a promising approach for treating HCC patients; however, its effectiveness needs to be improved. Recently, blockade of programmed death ligand 1 (PD-L1) immune checkpoint pathway has been shown to enhance anti-tumor immune responses and exhibited great potential in HCC therapy. Methods: In this study, we generated DC vaccine by pulsing the C57BL/6J mouse bone marrow-derived DC with mouse hepatoma Hep-55.1C cell lysate. We developed a therapeutic strategy combining DC vaccine and PD-L1 inhibitor for HCC and evaluated its efficacy in an orthotopic HCC mouse model in which Hep-55.1C cells were directly injected into left liver lobe of C57BL/6J mouse. Results: Compared with a control group of mice, groups of mice treated with DC vaccine or PD-L1 inhibitor had significantly improved overall survival, reduced tumor volume, and increased tumor cell apoptosis. Remarkably, combination treatment with DC vaccine and PD-L1 inhibitor led to considerably longer overall survival, smaller tumor volume, and higher tumor cell apoptosis of mice than either treatment alone in a dose-dependent manner through inducing a stronger anti-tumor cytotoxic T cell response. Conclusion: Our data suggested that combination therapy with DC vaccine and PD-L1 inhibitor might have great promise as a novel treatment strategy for HCC.

The role of dendritic cells in tumor microenvironments and their uses as therapeutic targets

“…In addition, PD-1 blockade increased the efficacy of DC vaccines when combined with tumor antigens and CCL21 in a mouse lung-cancer model ( 109 ). Furthermore, a combined treatment of DC vaccine and PD-L1 blockade improved overall survival and tumor rejection in a murine hepatocellular carcinoma model ( 110 ).…”

Combined vaccine-immune-checkpoint inhibition constitutes a promising strategy for treatment of dMMR tumors

“…Rare preclinical data exist on vaccine-α-PD-L1 combinations. A recent study described prolonged survival and increased tumor cell apoptosis in a hepatocellular carcinoma model treated with a combined DC vaccine and α-PD-L1 inhibitor [46], supported by findings from Ji et al, reporting reactivation of neoantigen-specific CTL by combined α-PD-L1 peptide vaccination [47]. Likewise, Sun et al found enhanced tumor-antigen-specific immunity upon combined vaccine-PD-L1-blockade [48].…”

Combined Vaccine-Immune-Checkpoint Inhibition Constitutes a Promising Strategy for Treatment of dMMR Tumors

“…Rare preclinical data exist on vaccine-α-PD-L1 combinations. A recent study described prolonged survival and increased tumor cell apoptosis in a hepatocellular carcinoma model treated with a combined DC vaccine and α-PD-L1 inhibitor [42]. Likewise, Sun et al found enhanced tumor-antigen-speci c immunity upon combined vaccine-PD-L1-blockade [43].…”