Immunomodulatory Effects of Endoscopic Ultrasound-Guided Thermal Ablation in Patients with Pancreatic Ductal Adenocarcinoma

SIMPLE SUMMARY: Thermal ablation under endoscopic ultrasound (EUS)-guidance has been investigated in pancreatic ductal adenocarcinoma (PDAC) based on its potential to boost local and systemic anti-tumor immune response. In a recent phase II randomized controlled trial, ablation of borderline resectable (BR) and locally advanced (LA) PDAC using the HybridTherm Probe (HTP) under EUS-guidance in combination with chemotherapy was shown to ameliorate disease progression at 6 months compared to chemotherapy alone. In this work, we aimed to explore the effects of EUS-ablation with HTP on the systemic immune response in patients with BR and LA PDAC. In contrast to chemotherapy, EUS-HTP selectively affected immunological predictors of poor outcome such as serum levels of APRIL/TNFSF13 and inflammatory monocytes, reinforcing its potential use in selected PDAC patients. ABSTRACT: Immunological consequences of endoscopic ultrasound (EUS)-local thermal ablation (LTA) for pancreatic ductal adenocarcinoma (PDAC) have not been extensively assessed. We aimed to explore EUS-LTA effects on the systemic immune response in PDAC. Peripheral blood was collected from 10 treatment-naïve patients with borderline resectable and locally advanced PDAC, randomly allocated to Nab-paclitaxel plus Gemcitabine chemotherapy (CT-arm, n = 5) or EUS-LTA with HybridTherm Probe plus CT (HTP + CT-arm, n = 5). Twenty healthy donors were included as controls. Flow-cytometry and multiplex assays were used to profile immune cell subsets and measure serum cytokines/chemokines, respectively. At baseline, PDAC patients showed increased circulating monocytes and lower circulating lymphocytes and CD19+ B cells counts compared to healthy controls. After 4 months, CT induced decrease of B regulatory cells, CD4+ cytotoxic T cells and IL-1β. The addition of EUS-HTP to CT selectively decreased the serum levels of APRIL/TNFSF13 as well as T regulatory cells, total, classic and inflammatory monocytes. Serum levels of APRIL/TNFSF13 and total, classic and inflammatory monocytes counts at baseline were associated with worse overall survival. EUS-HTP has the potential to selectively impact on immune cells and cytokines associated with poor outcomes in PDAC.