Induction of trained immunity by particulate β-glucan controls cancer metastasis through the sphingolipids-mediated mitochondrial fission pathway.

Abstract

Metastasis is the leading cause of cancer-related deaths and innate immune cells are critical players in the metastatic microenvironment. Here, we explore the implications of harnessing the pre-metastatic niche myeloid cells through induction of trained immunity using a natural compound yeast-derived whole β-glucan particle (WGP). WGP training in macrophages results in an increased responsiveness to not only the conventional secondary stimulus LPS but also specifically to tumor cells and tumor-derived factors. WGP in vivo treatment leads to a trained immunity phenotype in lung interstitial macrophages (IMs). Induction of trained immunity by WGP inhibits tumor metastasis and enhances tumor-free survival in multiple mouse models of tumor metastasis. Lung IMs trained with WGP exhibit increased phagocytic capacity and cytotoxicity against tumor cells in a ROS-dependent manner. Further studies reveal that WGP-induced trained immunity in lung IMs is mediated by a metabolite sphingosine-1-phosphate (S1P) through the sphingolipid synthesis pathway. S1P induces the phosphorylation of dynamin-related protein-1 (Drp-1) which is followed by mitochondrial fission to elicit a trained response. Inhibition of mitochondrial fission abrogates WGP-induced trained immunity and subsequent inhibition of lung metastases. WGP also induces trained immunity in human monocytes via the mitochondrial fission pathway. Collectively, our study identifies a novel metabolic sphingolipid synthesis-S1P-mediated mitochondrial fission pathway for WGP-induced trained immunity and metastasis control.