The induction of trained immunity through dietary supplementation with b-glucan boosts myeloid anti-tumour immunity in diet induced obesity

Abstract

Over the last 10 years, emerging concepts in our understanding of immunological memory have broadened the field to recognise that immunological memory is not a feature that is unique to the mammalian adaptive immune system. Innate immune memory, or trained immunity, is an evolving area of immunological research. b-glucans are activators of trained immunity, characterized by myelopoiesis and altered inflammatory responses upon rechallenge. Intra-peritoneal delivery of b-glucans has been shown to support anti-tumor function in mice. Little is known about the immunometabolic consequences of dietary b-glucans. High fat diets (HFDs) have also been reported to drive features of trained immunity. Diet induced obesity (DIO) is associated with increased tumour burden in mice, by impairing immunometabolic function of immune cells. We hypothesized that dietary delivery of a yeast derived whole glucan particle (WGP) could alter innate immune function by the induction of trained immunity and in the context of HFD, reverses defective anti-tumor immunity. Here we show that WGP feeding altered hematopoiesis, a hallmark of central trained immunity, leading to mature progeny with enhanced activities. This phenotype is maintained when mice are removed from the diet, suggesting dietary WGP feeding induces a trained immunity phenotype. Importantly, dietary WGP lowers tumour burden in mice. In WGP fed mice, an increase in the proportion of TNF producing intratumoural macrophages and monocytes was associated with a reduction in tumour burden. Similarly, intratumoural macrophages and monocytes display increased mitochondrial reactive oxygen species (mitoROS), which may aid in the reduction of tumours in these mice. Using a bone marrow transplantation model, the reduction in tumour burden in WGP fed mice was shown to be due to altered bone marrow hematopoiesis, with increasing mitoROS-producing macrophages in WGP-bone marrow transplanted mouse tumours. Moreover, when supplementing a HFD with WGP (HFD+WGP), the impaired anti-tumour responses observed in mice fed a HFD alone, were abolished in HFD+WGP mice. Analysis of intratumoural immune cells from mice fed HFD+WGP displayed enhanced anti-tumour responses in myeloid cells, with heightened TNF and mitoROS production. In vitro, WGP training increased glycolytic rates as well as basal oxidative phosphorylation (OXPHOS). Furthermore, WGP training in BMDMs increased phagocytic potential towards tumour cell lines and in direct and in direct stimulation with tumour cell lines, trained BMDMs increased mitoROS and TNF production. Ex vivo, BMDMs from mice fed HFD+WGP showed altered metabolic activity, with increased glycolytic rates and OXPHOS levels. This data suggests WGP supplementation may restore metabolic flexibility in myeloid cells, improving homeostatic function. Overall, feeding WGP induces trained immunity, enhancing myeloid anti-tumour function, without affecting the whole-body metabolic effects of obesity. Dietary WGP is a cost-effective means to reverse the immunometabolic defects of obesity which positions trained immunity-based strategies as promising adjunctive therapies in cancer.