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

IF 48.8 1区 医学 Q1 CELL BIOLOGY Cancer Cell Pub Date : 2024-09-09 DOI:10.1016/j.ccell.2024.08.008
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
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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.

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胶质母细胞瘤诱导颅骨骨髓中树突状 "混合 "中性粒细胞的招募和分化
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描述。我们在本文中展示了具有树突状特征的中性粒细胞--包括形态复杂性、抗原递呈基因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--在肿瘤内聚集并抑制体内肿瘤生长。对患者TAN scRNA-seq的轨迹分析发现,这种树突状细胞-中性粒细胞 "混合 "表型是一种有别于典型细胞毒性TAN的极化状态,它是从局部前体分化而来的。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了它们--不是从血液循环中产生,而是从局部颅骨骨髓中产生。通过标记颅骨瓣移植和靶向消融,我们确定了颅骨骨髓是抗肿瘤髓系抗原递呈细胞(APCs)的贡献者,其中包括能激发T细胞细胞毒性和记忆的TANs。因此,促进中性粒细胞从颅骨骨髓中排出的药物--如颅骨内AMD3100--具有治疗潜力。
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来源期刊
Cancer Cell
Cancer Cell 医学-肿瘤学
CiteScore
55.20
自引率
1.20%
发文量
179
审稿时长
4-8 weeks
期刊介绍: Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.
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