Harnessing the power of trained immunity using yeast-derived β-glucan to prevent pancreatic cancer

Abstract

Abstract Despite the remarkable success of immunotherapy, pancreatic cancer has yet to benefit. This creates a desperate need for therapies that target pancreatic cancer and utilize novel approaches to prevent and treat this lethal disease. Innate immune cells are vital in antitumor immunosurveillance. Recent studies have shown that innate immune cells possess a form of memory termed Trained Immunity (TI), where cells exposed to an initial stimulus undergo epigenetic and metabolic reprograming that causes hyper-responsiveness when exposed to a second signal. It is yet unknown whether inducing TI could protect against tumors, and specifically pancreatic tumors. Here we show that yeast-derived particulate β-glucan, a known TI inducer, results in 90% of an intraperitoneal dose trafficking to the pancreas. This leads to a robust, dose-dependent influx of innate and adaptive immune cells into the pancreas that have enhanced Th1 function. Despite the cellular influx, signs of pancreatitis are absent. In vivo and in vitro studies of β-glucan trained pancreatic macrophages show increased TNFα and IL-6 production when exposed to LPS, pancreatic tumor cells and their supernatant. This indicates that pancreatic macrophages can be trained to protect against pancreatic tumor cells. Depletion of various immune populations suggest that pancreatic macrophages are directly trained by β-glucan, which then stimulate NK and T-cells. In an orthotopic model of pancreatic cancer, β-glucan trained mice show reduced tumor burden and augmented antitumor functions of innate and adaptive cells. Together, this suggests that β-glucan can train pancreatic innate immune cells to have antitumor memory, which can serve as a novel approach to treating pancreatic cancer.