Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Nat Commun. 2023 Apr 3;14(1):1839. doi: 10.1038/s41467-023-37361-8.
Myeloid cells comprise the majority of immune cells in tumors, contributing to tumor growth and therapeutic resistance. Incomplete understanding of myeloid cells response to tumor driver mutation and therapeutic intervention impedes effective therapeutic design. Here, by leveraging CRISPR/Cas9-based genome editing, we generate a mouse model that is deficient of all monocyte chemoattractant proteins. Using this strain, we effectively abolish monocyte infiltration in genetically engineered murine models of de novo glioblastoma (GBM) and hepatocellular carcinoma (HCC), which show differential enrichment patterns for monocytes and neutrophils. Eliminating monocyte chemoattraction in monocyte enriched PDGFB-driven GBM invokes a compensatory neutrophil influx, while having no effect on Nf1-silenced GBM model. Single-cell RNA sequencing reveals that intratumoral neutrophils promote proneural-to-mesenchymal transition and increase hypoxia in PDGFB-driven GBM. We further demonstrate neutrophil-derived TNF-a directly drives mesenchymal transition in PDGFB-driven primary GBM cells. Genetic or pharmacological inhibiting neutrophils in HCC or monocyte-deficient PDGFB-driven and Nf1-silenced GBM models extend the survival of tumor-bearing mice. Our findings demonstrate tumor-type and genotype dependent infiltration and function of monocytes and neutrophils and highlight the importance of targeting them simultaneously for cancer treatments.
髓系细胞构成了肿瘤中大多数免疫细胞，促进肿瘤生长和治疗抵抗。对髓系细胞对肿瘤驱动突变和治疗干预的反应的不完全理解阻碍了有效的治疗设计。在这里，我们利用基于 CRISPR/Cas9 的基因组编辑，生成了一种缺乏所有单核细胞趋化蛋白的小鼠模型。利用这种品系，我们有效地消除了从头胶质母细胞瘤（GBM）和肝细胞癌（HCC）的基因工程小鼠模型中的单核细胞浸润，这些模型显示单核细胞和中性粒细胞的富集模式存在差异。在单核细胞富集的 PDGFB 驱动的 GBM 中消除单核细胞趋化作用会引起代偿性中性粒细胞流入，而对 NF1 沉默的 GBM 模型没有影响。单细胞 RNA 测序显示，肿瘤内中性粒细胞促进了 PDGFB 驱动的 GBM 中的神经前体细胞向间充质转化，并增加了缺氧。我们进一步证明中性粒细胞衍生的 TNF-a 可直接驱动 PDGFB 驱动的原发性 GBM 细胞的间充质转化。在 HCC 或单核细胞缺乏的 PDGFB 驱动和 NF1 沉默的 GBM 模型中，遗传或药理学抑制中性粒细胞可延长荷瘤小鼠的存活时间。我们的研究结果表明，单核细胞和中性粒细胞的浸润和功能依赖于肿瘤类型和基因型，并强调了同时靶向它们治疗癌症的重要性。
