文章：

VISTA作为对抗髓母细胞瘤免疫逃逸机制的有前景靶点崭露头角

VISTA Emerges as a Promising Target against Immune Evasion Mechanisms in Medulloblastoma

原文发布日期：24 July 2024

DOI: 10.3390/cancers16152629

类型: Article

开放获取: 是

英文摘要：

Background: Relapsed medulloblastoma (MB) poses a significant therapeutic challenge due to its highly immunosuppressive tumor microenvironment. Immune checkpoint inhibitors (ICIs) have struggled to mitigate this challenge, largely due to low T-cell infiltration and minimal PD-L1 expression. Identifying the mechanisms driving low T-cell infiltration is crucial for developing more effective immunotherapies. Methods: We utilize a syngeneic mouse model to investigate the tumor immune microenvironment of MB and compare our findings to transcriptomic and proteomic data from human MB. Results: Flow cytometry reveals a notable presence of CD45hi/CD11bhimacrophage-like and CD45int/CD11bintmicroglia-like tumor-associated macrophages (TAMs), alongside regulatory T-cells (Tregs), expressing high levels of the inhibitory checkpoint molecule VISTA. Compared to sham control mice, the CD45hi/CD11bhicompartment significantly expands in tumor-bearing mice and exhibits a myeloid-specific signature composed of VISTA, CD80, PD-L1, CTLA-4, MHCII, CD40, and CD68. These findings are corroborated by proteomic and transcriptomic analyses of human MB samples. Immunohistochemistry highlights an abundance of VISTA-expressing myeloid cells clustering at the tumor–cerebellar border, while T-cells are scarce and express FOXP3. Additionally, tumor cells exhibit immunosuppressive properties, inhibiting CD4 T-cell proliferation in vitro. Identification of VISTA’s binding partner, VSIG8, on tumor cells, and its correlation with increased VISTA expression in human transcriptomic analyses suggests a potential therapeutic target. Conclusions: This study underscores the multifaceted mechanisms of immune evasion in MB and highlights the therapeutic potential of targeting the VISTA–VSIG axis to enhance anti-tumor responses.

摘要翻译： 

背景：复发性髓母细胞瘤（MB）因其高度免疫抑制的肿瘤微环境而构成显著的治疗挑战。免疫检查点抑制剂（ICIs）在应对这一挑战方面收效有限，主要归因于T细胞浸润程度低且PD-L1表达极少。明确导致T细胞低浸润的机制对于开发更有效的免疫疗法至关重要。 方法：我们利用同基因小鼠模型研究MB的肿瘤免疫微环境，并将研究结果与人类MB的转录组学和蛋白质组学数据进行比较。 结果：流式细胞术分析显示，存在大量表达高水平抑制性检查点分子VISTA的CD45hi/CD11bhi巨噬细胞样和CD45int/CD11bint小胶质细胞样肿瘤相关巨噬细胞（TAMs），以及调节性T细胞（Tregs）。与假手术对照组小鼠相比，荷瘤小鼠的CD45hi/CD11bhi细胞群显著扩增，并表现出由VISTA、CD80、PD-L1、CTLA-4、MHCII、CD40和CD68组成的髓系特异性特征。对人类MB样本的蛋白质组学和转录组学分析证实了这些发现。免疫组织化学分析显示，大量表达VISTA的髓系细胞聚集在肿瘤与小脑交界处，而T细胞稀少且表达FOXP3。此外，肿瘤细胞表现出免疫抑制特性，在体外能抑制CD4 T细胞增殖。在肿瘤细胞上鉴定出VISTA的结合配体VSIG8，以及人类转录组学分析中其与VISTA表达增加的相关性，提示了潜在的治疗靶点。 结论：本研究揭示了MB中多方面的免疫逃逸机制，并强调了靶向VISTA-VSIG轴以增强抗肿瘤反应的治疗潜力。

原文链接：

VISTA Emerges as a Promising Target against Immune Evasion Mechanisms in Medulloblastoma