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

Abstract

SUMMARYTumor-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 growthin 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.