Radiofrequency ablation in combination with an mTOR inhibitor restrains pancreatic cancer growth induced by intrinsic HSP70.

Abstract

Background:Radiofrequency ablation (RFA) is widely used in palliative therapy of malignant cancers. Several studies have shown its applicability and safety for locally advanced pancreatic cancer (LAPC). The objective of this study was to modify the current regimen to improve its therapeutic effect.Methods:Immune cell subtypes and related cytokines were quantified to uncover the immune pattern changes post-RFA treatment. Then, high-throughput proteome analysis was performed to identify differentially expressed proteins associated with RFA, which were further validated in in vitro and in vivo experiments. Finally, a combined therapy was tested in a murine model to observe its therapeutic effect.Results:In preclinical murine models of RFA treatment, no significant therapeutic benefit was observed following RFA treatment. However, the proportion of tumor-infiltrating CD8+ T cells was significantly increased, whereas that of regulatory T cells (Tregs) was decreased post-RFA treatment, which indicated a beneficial anti-tumor environment. To identify the mechanism, high-throughput mass spectrum was obtained that identified heat shock protein 70 (HSP70) as the top differentially expressed protein. HSP70 expression in residual cancer cells was significantly increased post-RFA treatment, which notably promoted pancreatic cancer growth. Elevated HSP70 promoted cell proliferation by activating AKT–mTOR signaling. Finally, RFA treatment combined with an mTOR inhibitor exerted a synergetic repressive effect on tumor growth in the preclinical murine cancer model.Conclusions:RFA treatment in combination with mTOR signaling blockade can not only promote tumor immune response, but also restrain residual cancer cell proliferation. Such a combination may be a promising and effective therapeutic strategy for LAPC patients.