Glioblastoma induces the recruitment and differentiation of hybrid neutrophils from skull bone marrow
Lad, M.; Beniwal, A.; Jain, S.; Shukla, P.; Jung, J.; Shah, S.; Yagnik, G.; Babikir, H.; Nguyen, A. T.; Gill, S.; Young, J. S.; Lui, A.; Salha, D.; Diaz, A.; Aghi, M. K.
Show 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.
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