Glioblastoma (GBM) is the most common malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized 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 cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a subset of myeloid cells, expressing monocytic (M)-MDSC markers and dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate the TME. This study evaluated the mechanism of CCR2+/CX3CR1+M-MDSC differentiation and T cell suppressive function in murine glioma models. We determined that bone marrow-derived CCR2+/CX3CR1+cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Glioma-secreted CSF1R ligands M-CSF and IL-34 were identified as key drivers of M-MDSC differentiation while adenosine and iNOS pathways were implicated in the M-MDSC suppression of T cells. Mining a human GBM spatial RNAseq database revealed a variety of different pathways that M-MDSCs utilize to exert their suppressive function that is driven by complex niches within the microenvironment. These data provide a more comprehensive understanding of the mechanism of M-MDSCs in glioblastoma.
胶质母细胞瘤（GBM）是最常见的恶性原发性脑肿瘤，即使采用积极治疗，患者生存率仍然较低。GBM的特征在于其高度异质性和免疫抑制性的肿瘤微环境（TME），该环境主要由浸润的外周免疫细胞构成。其中，一类被称为髓源性抑制细胞（MDSCs）的免疫抑制细胞在胶质瘤免疫逃逸中发挥重要作用。先前研究表明，表达单核细胞（M）-MDSC标志物及趋化因子受体CCR2与CX3CR1双阳性的髓系细胞亚群，利用CCR2浸润至TME。本研究通过小鼠胶质瘤模型评估了CCR2+/CX3CR1+ M-MDSC的分化机制及其对T细胞的抑制功能。实验发现，骨髓来源的CCR2+/CX3CR1+细胞在与胶质瘤来源因子共培养时，会呈现免疫抑制细胞表型。胶质瘤分泌的CSF1R配体M-CSF和IL-34被确定为驱动M-MDSC分化的关键因素，而腺苷和一氧化氮合酶（iNOS）通路则参与M-MDSC对T细胞的抑制过程。通过对人类GBM空间转录组数据库的分析，揭示了M-MDSCs利用微环境中复杂生态位驱动的多种不同通路发挥其免疫抑制功能。这些数据为深入理解胶质母细胞瘤中M-MDSCs的作用机制提供了更全面的视角。
肿瘤(癌症)患者之家