Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity

TLDR

Trained innate immunity, induced by modulating myeloid cells or their progenitors, sustains heightened responsiveness to subsequent challenges. The study examined whether inducing trained immunity could boost anti‑tumor immunity. β‑glucan pre‑treatment suppressed tumor growth by reprogramming granulopoiesis and neutrophils toward an anti‑tumor phenotype, a process dependent on type I interferon signaling, ROS production, and transmissible via bone‑marrow transfer.

Abstract

Trained innate immunity, induced via modulation of mature myeloid cells or their bone marrow progenitors, mediates sustained increased responsiveness to secondary challenges. Here, we investigated whether anti-tumor immunity can be enhanced through induction of trained immunity. Pre-treatment of mice with β-glucan, a fungal-derived prototypical agonist of trained immunity, resulted in diminished tumor growth. The anti-tumor effect of β-glucan-induced trained immunity was associated with transcriptomic and epigenetic rewiring of granulopoiesis and neutrophil reprogramming toward an anti-tumor phenotype; this process required type I interferon signaling irrespective of adaptive immunity in the host. Adoptive transfer of neutrophils from β-glucan-trained mice to naive recipients suppressed tumor growth in the latter in a ROS-dependent manner. Moreover, the anti-tumor effect of β-glucan-induced trained granulopoiesis was transmissible by bone marrow transplantation to recipient naive mice. Our findings identify a novel and therapeutically relevant anti-tumor facet of trained immunity involving appropriate rewiring of granulopoiesis.