IDDF2018-ABS-0132 Irreversible electroporation induces immunogenic cell death in hepatocellular carcinoma and promotes systemic anti-tumour immune effects in mice models

    loading  Checking for direct PDF access through Ovid

Abstract

Background

The therapeutic efficacy of ablation on hepatocellular carcinoma (HCC) is impeded due to high tumour recurrence. The immune response induced by ablation has provided new insights into tumour monitoring and elimination. Irreversible electroporation (IRE) ablates tumours through high frequency electric pulse in a non-thermal manner, which could preserve more intact tumour antigens and provide a more powerful anti-tumour immune response theoretically. We aimed to explore the effects of immune reaction mediated by IRE.

Methods

In vitro, characteristics of HCC cell death were determined by trypan blue staining, flow cytometrys (FCS) and transmission electron microscope analysis. Immunogenic cell death (ICD) was detected by calreticulin or HSP70 exposure by FCS, ATP secretion by luciferase and DC maturation assay. In vivo, C57BL/6 mice were employed to establish tumour ablation model, in which dynamics of immune infiltration were analysed by FCS and immunohistochemistry. The adaptive immune response was further confirmed by CD8 blockade, and vaccine experiments were performed.

Results

We found that IRE ablation could effectively result in HCC cell death via necrosis and induced positive molecular determinants of ICD including increased ecto-CRT and ecto-HSP70 exposure and elevated extracellular ATP level. In addition, the dendritic cells co-cultured with IRE-induced tumour lysis were activated evidenced by upexpression of co-stimulators and increased secretion of cytokine. Using mice model, we found IRE significantly inhibited tumour growth accompanied by increased CD8 +IFN- γ +T cells and reduced PD-1 +cells and Treg. Depletion of CD8 +T cells abolished the therapeutic effect of IRE that local tumour recurrence and distant metastasis were promoted. IRE-based vaccine experiments showed vaccinated mice significantly resisted secondary tumour induction and demonstrated a long-term immunological memory response.

Conclusions

Our study revealed that IRE treatment trigged ICD, enhanced immune response upon tumour recurrence and distant metastasis through CD8 +T cells and induced alleviation of immunosuppression.

Related Topics

    loading  Loading Related Articles