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核心技术专利：CN118964589B侵权必究
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胶质母细胞瘤衍生的 CCL2 和 CCL7 以冗余方式介导免疫抑制性 CCR2/CX3CR1 M-MDSC 向肿瘤微环境迁移。

Glioma-derived CCL2 and CCL7 mediate migration of immune suppressive CCR2/CX3CR1 M-MDSCs into the tumor microenvironment in a redundant manner.

机构信息

Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, FL, United States.

Department of Neurosurgery, University of Florida College of Medicine, Gainesville, FL, United States.

出版信息

Front Immunol. 2023 Jan 4;13:993444. doi: 10.3389/fimmu.2022.993444. eCollection 2022.

DOI:10.3389/fimmu.2022.993444
PMID:36685592
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9854274/
Abstract

Glioblastoma (GBM) is the most common and malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized in part by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive, hematopoietic cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a potent subset of myeloid cells, expressing monocytic (M)-MDSC markers, distinguished by dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate into the TME. This study evaluated the T cell suppressive function and migratory properties of CCR2/CX3CR1 MDSCs. Bone marrow-derived CCR2/CX3CR1 cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Recombinant and glioma-derived CCL2 and CCL7 induce the migration of CCR2/CX3CR1 MDSCs with similar efficacy. KR158B-CCL2 and -CCL7 knockdown murine gliomas contain equivalent percentages of CCR2/CX3CR1 MDSCs compared to KR158B gliomas. Combined neutralization of CCL2 and CCL7 completely blocks CCR2-expressing cell migration to KR158B cell conditioned media. CCR2/CX3CR1 cells are also reduced within KR158B gliomas upon combination targeting of CCL2 and CCL7. High levels of CCL2 and CCL7 are also associated with negative prognostic outcomes in GBM patients. These data provide a more comprehensive understanding of the function of CCR2/CX3CR1 MDSCs and the role of CCL2 and CCL7 in the recruitment of these immune suppressive cells and further support the significance of targeting this chemokine axis in GBM.

摘要

胶质母细胞瘤（GBM）是最常见和恶性的原发性脑肿瘤，尽管采用了积极的治疗方法，但生存率仍然很差。GBM 的部分特征是高度异质性和免疫抑制的肿瘤微环境（TME），主要由浸润的外周免疫细胞组成。一种对胶质瘤免疫逃逸有重要贡献的重要免疫细胞类型是一群免疫抑制性造血细胞，称为髓系来源的抑制细胞（MDSC）。先前的研究表明，表达单核细胞（M）-MDSC 标志物的髓系细胞的一个有效亚群，通过趋化因子受体 CCR2 和 CX3CR1 的双重表达来区分，利用 CCR2 浸润到 TME 中。本研究评估了 CCR2/CX3CR1 MDSC 的 T 细胞抑制功能和迁移特性。当与胶质瘤衍生因子共培养时，骨髓来源的 CCR2/CX3CR1 细胞采用免疫抑制细胞表型。重组和胶质瘤衍生的 CCL2 和 CCL7 以相似的效力诱导 CCR2/CX3CR1 MDSC 的迁移。与 KR158B 胶质瘤相比，KR158B-CCL2 和 -CCL7 敲低的鼠胶质瘤中含有相同百分比的 CCR2/CX3CR1 MDSC。CCL2 和 CCL7 的联合中和完全阻止了 CCR2 表达细胞向 KR158B 细胞条件培养基的迁移。在 CCL2 和 CCL7 的联合靶向作用下，KR158B 胶质瘤内的 CCR2/CX3CR1 细胞也减少。CCL2 和 CCL7 的高水平也与 GBM 患者的不良预后结果相关。这些数据提供了对 CCR2/CX3CR1 MDSC 功能以及 CCL2 和 CCL7 在招募这些免疫抑制细胞中的作用的更全面的理解，并进一步支持靶向该趋化因子轴在 GBM 中的重要性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cad0/9854274/abf39f9b17b0/fimmu-13-993444-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cad0/9854274/09569087f3e9/fimmu-13-993444-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cad0/9854274/1d0f2f8826cb/fimmu-13-993444-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cad0/9854274/0a1fa0d1c1f9/fimmu-13-993444-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cad0/9854274/140897bd92ce/fimmu-13-993444-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cad0/9854274/9b516dc9166c/fimmu-13-993444-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cad0/9854274/abf39f9b17b0/fimmu-13-993444-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cad0/9854274/09569087f3e9/fimmu-13-993444-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cad0/9854274/1d0f2f8826cb/fimmu-13-993444-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cad0/9854274/0a1fa0d1c1f9/fimmu-13-993444-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cad0/9854274/140897bd92ce/fimmu-13-993444-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cad0/9854274/9b516dc9166c/fimmu-13-993444-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cad0/9854274/abf39f9b17b0/fimmu-13-993444-g006.jpg

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[9]
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本文引用的文献

[1]
Systemic Delivery of an Adjuvant CXCR4-CXCL12 Signaling Inhibitor Encapsulated in Synthetic Protein Nanoparticles for Glioma Immunotherapy.

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Distinct Populations of Immune-Suppressive Macrophages Differentiate from Monocytic Myeloid-Derived Suppressor Cells in Cancer.

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