Glioblastoma induces the recruitment and differentiation of hybrid neutrophils from skull bone marrow

Abstract

Tumor-associated neutrophil (TAN) effects on glioblastoma biology remain under-characterized. We show here that 'hybrid' neutrophils with dendritic features - including morphological complexity, expression of antigen presentation genes, and the ability to process exogenous peptide and stimulate MHCII-dependent T cell activation - accumulate intratumorally and suppress tumor growth in vivo. Trajectory analysis of patient TAN scRNA-seq identifies this phenotype as a polarization state which is distinct from canonical cytotoxic TANs and differentiates intratumorally from immature precursors absent in circulation. Rather, these hybrid-inducible immature neutrophils - which we identified in patient and murine glioblastomas - arise from local skull marrow. Through labeled skull flap transplantation and targeted ablation, we characterize calvarial marrow as a potent contributor of antitumoral myeloid APCs, including hybrid TANs and dendritic cells, which elicit T cell cytotoxicity and memory. As such, agents augmenting neutrophil egress from skull marrow - such as intracalvarial AMD3100 whose survival prolonging-effect in GBM we demonstrate - present therapeutic potential.

Neutrophils in glioma microenvironment: from immune function to immunotherapy

“…In 2023, Meeki Ld et al. further confirmed the recruitment of TANs from the skull in GBM ( 21 ). They proposed that the role of the skull in supplying immune cells to the GBM TME is pronounced, and that systemic bone marrow sites could not adequately compensate for the absence of skull marrow.…”

“…In 2021, Andrea Cugurra et al demonstrated that neutrophils originated from cranial and vertebral bone marrow can migrate to the meninges and parenchyma via ossified channels containing blood vessels (19, 20). In 2023, Meeki Ld et al further confirmed the recruitment of TANs from the skull in GBM (21). They proposed that the role of the skull in supplying immune cells to the GBM TME is pronounced, and that systemic bone marrow sites could not adequately compensate for the absence of skull marrow.…”

Glioma–Immune Cell Crosstalk in Tumor Progression

“…Gliomas can induce peripheral neutrophilia through the secretion of granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) [68]. Recent work by Lad et al has also demonstrated that GM-CSF in the glioblastoma secretome enhances the longevity of peripheral blood neutrophils [69]. In addition to enhancing granulopoiesis, gliomas can recruit neutrophils to the TME through expression of high levels of IL-8, under stimulation of IL-1, TNFα, and high-mobility group box 1 (HMGB1) derived from NETs [70,71].…”

“…However, this anti-tumor effect was lost with tumor progression. Interestingly, Lad et al recently showed that a subset of TANs are recruited from skull marrow and uniquely differentiate into APC-like cells that activate T-cells and suppress tumor growth [69]. A more detailed understanding of neutrophils and other granulocytes and signals that pivot neutrophils to become immunosuppressive may hold promise for a better understanding of the reprogramming system of the TME and new potential immunotherapy targets.…”