美国加州大学旧金山分校Manish K. Aghi研究团队发现，胶质母细胞瘤诱导来自颅骨骨髓的树突状“混合”中性粒细胞的招募和分化。2024年9月9日出版的《癌细胞》杂志发表了这项成果。

据介绍，TAN对GBM生物学的影响仍未得到充分表征。研究人员发现，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细胞激活的能力——在肿瘤内积累，并在体内抑制肿瘤生长。

患者肿瘤相关中性粒细胞（TAN）的单细胞RNA测序轨迹分析表明，这种“混合”树突状-中性粒细胞表型是不同于经典细胞毒性TAN的极化状态，并从局部前体细胞分化而来。这些在患者和小鼠胶质母细胞瘤中发现的可诱导的混合未成熟中性粒细胞并非来自循环系统，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实验，研究人员确定了颅骨骨髓是抗肿瘤髓系抗原呈递细胞（APC）的来源，包括TAN，这些细胞能够引发T细胞的细胞毒性和记忆。因此，增强中性粒细胞从颅骨骨髓迁出的药物，如该研究发现的在胶质母细胞瘤（GBM）中延长生存的颅内AMD3100，显示了潜在的治疗前景。

附：英文原文

Title: Glioblastoma induces the recruitment and differentiation of dendritic-like “hybrid” neutrophils from skull bone marrow

Author: Meeki Lad, Angad S. Beniwal, Saket Jain, Poojan Shukla, Venina Kalistratova, Jangham Jung, Sumedh S. Shah, Garima Yagnik, Atul Saha, Ankita Sati, Husam Babikir, Alan T. Nguyen, Sabraj Gill, Jennifer Rios, Jacob S. Young, Austin Lui, Diana Salha, Aaron Diaz, Manish K. Aghi

Issue&Volume: 2024/09/09

Abstract: 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.

DOI: 10.1016/j.ccell.2024.08.008

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00307-6