Glioblastoma induces the recruitment and differentiation of dendritic-like “hybrid” neutrophils from skull bone marrow,Cancer Cell

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Glioblastoma induces the recruitment and differentiation of dendritic-like “hybrid” neutrophils from skull bone marrow
Cancer Cell ( IF 48.8 ) Pub Date : 2024-09-09 , DOI: 10.1016/j.ccell.2024.08.008
Meeki Lad ₁ , Angad S Beniwal ₁ , Saket Jain ₁ , Poojan Shukla ₁ , Venina Kalistratova ₁ , Jangham Jung ₁ , Sumedh S Shah ₁ , Garima Yagnik ₁ , Atul Saha ₁ , Ankita Sati ₁ , Husam Babikir ₁ , Alan T Nguyen ₁ , Sabraj Gill ₁ , Jennifer Rios ₁ , Jacob S Young ₁ , Austin Lui ₁ , Diana Salha ₁ , Aaron Diaz ₁ , Manish K Aghi ₁

Affiliation

Tumor-associated neutrophil (TAN) effects on glioblastoma (GBM) biology remain under-characterized. We show here that neutrophils with dendritic features—including morphological complexity, expression of antigen presentation genes, and the ability to process exogenous peptide and stimulate major histocompatibility complex (MHC)II-dependent T cell activation—accumulate intratumorally and suppress tumor growth in vivo. Trajectory analysis of patient TAN scRNA-seq identifies this “hybrid” dendritic-neutrophil phenotype as a polarization state that is distinct from canonical cytotoxic TANs, and which differentiates from local precursors. These hybrid-inducible immature neutrophils—which we identified in patient and murine glioblastomas—arise not from circulation, but from local skull marrow. Through labeled skull flap transplantation and targeted ablation, we characterize calvarial marrow as a contributor of antitumoral myeloid antigen-presenting cells (APCs), including TANs, 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 report—present therapeutic potential.

中文翻译：

胶质母细胞瘤诱导颅骨骨髓中树突状“混合”中性粒细胞的募集和分化

肿瘤相关中性粒细胞 (TAN) 对胶质母细胞瘤 (GBM) 生物学的影响仍未得到充分表征。我们在这里展示了具有树突状特征的中性粒细胞——包括形态复杂性、抗原呈递基因的表达以及处理外源肽和刺激主要组织相容性复合体（MHC）II依赖性T细胞活化的能力——在肿瘤内积累并抑制体内肿瘤生长。对患者 TAN scRNA-seq 的轨迹分析将这种“混合”树突状-中性粒细胞表型识别为极化状态，与典型的细胞毒性 TAN 不同，并且与局部前体细胞不同。这些混合诱导的未成熟中性粒细胞（我们在患者和小鼠胶质母细胞瘤中发现）不是来自循环系统，而是来自局部颅骨骨髓。通过标记的颅骨瓣移植和靶向消融，我们将颅骨骨髓描述为抗肿瘤髓样抗原呈递细胞（APC）的贡献者，其中包括 TAN，可引发 T 细胞的细胞毒性和记忆。因此，增加中性粒细胞从颅骨中流出的药物（例如颅内注射 AMD3100，我们报告了其对 GBM 的生存延长作用）具有治疗潜力。

更新日期：2024-09-09

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