Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity

Abstract

Summary 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.

Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities

“…Whether this type I interferon-associated hyper-reactivity of peripheral blood neutrophils from patients with periodontitis arises from trained granulopoiesis in the bone marrow is uncertain. Interestingly, mice systemically treated with fungally derived β-glucan, a known inducer of trained immunity, display type I interferon-dependent trained granulopoiesis with transcriptomic and epigenetic rewiring of granulopoietic progenitors in the bone marrow, leading to the generation of neutrophils with an enhanced ROS-dependent tumour-killing phenotype 81 . Thus, trained granulopoiesis induced by systemic inflammation (due to treatment with purified agonists or perhaps associated with periodontitis or other condition) might lead to the generation of hyper-reactive neutrophils, which, depending on the disease context, can be protective (for example, in tumour immunity) or destructive (for instance, in inflammatory conditions).…”

High dimensional profiling identifies specific immune types along the recovery trajectories of critically ill COVID19 patients

“…As such, it has been shown that COVID-19 leads to the combination of pathologically elevated levels of pro-inflammatory cytokines, coagulopathy and a dysregulated immune response [ 6 , 8 , 9 ]. Deep immune-profiling in severe COVID-19 patients revealed excessive amounts of dysfunctional neutrophils, decreased levels of lymphocytes and low levels of antigen-presenting receptors on monocytes and dendritic cells, hindering efficient adaptive immune responses [ 8 , 10 – 12 ]. In contrast to asymptomatic or mild/moderate symptomatic COVID-19 patients, critically ill patients typically show a biphasic disease course with an early viral stage before ICU admission, followed by a hypoxic phase characterized by a cytokine storm and acute respiratory distress requiring (invasive) respiratory support, antivirals and immune modulation to prevent multiple organ failure and death.…”

Neutrophils as Orchestrators in Tumor Development and Metastasis Formation

“…Trained granulopoiesis was mediated by type I IFN signaling, while the tumor suppressive activity of “trained” neutrophils was mediated by enhanced ROS production. The therapeutic potential of ‘trained’ neutrophils was confirmed by the decreased tumor growth in mice that received neutrophils from β-glucan–treated donor mice ( 128 ).…”