Trained innate immunity fosters a sustained favorable response of myeloid cells to a secondary challenge, despite their short lifespan in circulation. We thus hypothesized that trained immunity acts via modulation of hematopoietic stem and progenitor cells (HSPCs). Administration of β-glucan (prototypical trained-immunity-inducing agonist) to mice induced expansion of progenitors of the myeloid lineage, which was associated with elevated signaling by innate immune mediators, such as IL-1β and granulocyte-macrophage colony-stimulating factor (GM-CSF), and with adaptations in glucose metabolism and cholesterol biosynthesis. The trained-immunity-related increase in myelopoiesis resulted in a beneficial response to secondary LPS challenge and protection from chemotherapy-induced myelosuppression in mice. Therefore, modulation of myeloid progenitors in the bone marrow is an integral component of trained immunity, which to date, was considered to involve functional changes of mature myeloid cells in the periphery.

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.

Recent advances have highlighted the ability of hematopoietic stem and progenitor cells in the bone marrow to sense peripheral inflammation or infection and adapt through increased proliferation and skewing toward the myeloid lineage. Such adaptations can meet the increased demand for innate immune cells and can be beneficial in response to infection or myeloablation. However, the inflammation-induced adaptation of hematopoietic and myeloid progenitor cells toward enhanced myelopoiesis might also perpetuate inflammation in chronic inflammatory or cardio-metabolic diseases by generating a feed-forward loop between inflammation-adapted hematopoietic progenitor cells and the inflammatory disorder. Sustained adaptive responses of progenitor cells in the bone marrow can also contribute to trained immunity, a non-specific memory of earlier encounters that in turn facilitates the heightened response of these cells, as well as that of their progeny, to future challenges. Here we discuss the mechanisms that govern the adaptation of hematopoietic progenitor cells to inflammation and its sequelae in the pathogenesis of human disease.