The comparable tumour microenvironment in sporadic and NF2-related schwannomatosis vestibular schwannoma.
The comparable tumour microenvironment in sporadic and NF2-related schwannomatosis vestibular schwannoma.
复制标题
DOI：
10.1093/braincomms/fcad197
复制
发表时间：
2023
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
--
作者：
双侧前庭神经鞘瘤是 NF2 相关神经鞘瘤病的标志，这是一种罕见的肿瘤易感综合征，与终生的手术干预、放射治疗和抗血管生成药物贝伐单抗的超说明书使用相关。单侧前庭神经鞘瘤在非 NF2 相关神经鞘瘤病患者中偶发，目前尚无可用的药物治疗选择。巨噬细胞和 T 细胞等肿瘤浸润免疫细胞与前庭神经鞘瘤生长增加相关，这在散发性和 NF2 相关神经鞘瘤病肿瘤中是相似的。然而，NF2 相关神经鞘瘤病和更常见的散发性疾病之间的差异包括 NF2 相关神经鞘瘤病患者的肿瘤数量增加、肿瘤类型多种且诊断时年龄较小。因此，需要对散发性和 NF2 相关神经鞘瘤病肿瘤的肿瘤微环境进行比较，以支持免疫治疗靶点的开发，确定将散发性前庭神经鞘瘤的离体数据外推到 NF2 相关神经鞘瘤病的可能性，并帮助为临床试验设计提供信息，以了解共同招募散发性和 NF2 相关神经鞘瘤病患者的可行性。这项研究汇集了来自三个已发表的 Affymetrix 微阵列数据集的大量转录组数据，以比较散发性和 NF2 相关神经鞘瘤病前庭神经鞘瘤的基因表达谱，然后进行反卷积以预测不同肿瘤免疫微环境群体的丰度。使用定量 PCR 和 Hyperion 成像质谱流式细胞术验证数据。比较生物信息学分析揭示了三个数据集中 NF2 相关神经鞘瘤病和散发性前庭神经鞘瘤的密切相似性。在 NF2 相关神经鞘瘤病和散发性前庭神经鞘瘤中，重要的炎症标志物和信号通路密切匹配，与巨噬细胞增殖、血管生成和炎症有关。大量转录组学和成像质谱流式细胞术数据确定巨噬细胞是前庭神经鞘瘤中最丰富的免疫群体，占 NF2 相关神经鞘瘤病和散发性肿瘤细胞量的三分之一。重要的是，NF2相关神经鞘瘤病和散发性前庭神经鞘瘤之间的信号通路、基因表达、细胞类型丰度或成像质量流式细胞术染色没有显着差异。这些数据表明 NF2 相关神经鞘瘤病和散发性前庭神经鞘瘤的肿瘤免疫微环境有很强的相似性。前庭神经鞘瘤是在 NF2 相关神经鞘瘤病患者和非 NF2 相关神经鞘瘤病散发患者中发现的脑肿瘤。格雷戈里等人。发现 NF2 相关神经鞘瘤病和散发性前庭神经鞘瘤的细胞类型、血管、基因表达和炎症通路有很强的相似性；因此，药物和临床试验对两组患者可能同样有效。
Bilateral vestibular schwannoma is the hallmark of NF2-related schwannomatosis, a rare tumour predisposition syndrome associated with a lifetime of surgical interventions, radiotherapy and off-label use of the anti-angiogenic drug bevacizumab. Unilateral vestibular schwannoma develops sporadically in non-NF2-related schwannomatosis patients for which there are no drug treatment options available. Tumour-infiltrating immune cells such as macrophages and T-cells correlate with increased vestibular schwannoma growth, which is suggested to be similar in sporadic and NF2-related schwannomatosis tumours. However, differences between NF2-related schwannomatosis and the more common sporadic disease include NF2-related schwannomatosis patients presenting an increased number of tumours, multiple tumour types and younger age at diagnosis. A comparison of the tumour microenvironment in sporadic and NF2-related schwannomatosis tumours is therefore required to underpin the development of immunotherapeutic targets, identify the possibility of extrapolating ex vivo data from sporadic vestibular schwannoma to NF2-related schwannomatosis and help inform clinical trial design with the feasibility of co-recruiting sporadic and NF2-related schwannomatosis patients. This study drew together bulk transcriptomic data from three published Affymetrix microarray datasets to compare the gene expression profiles of sporadic and NF2-related schwannomatosis vestibular schwannoma and subsequently deconvolved to predict the abundances of distinct tumour immune microenvironment populations. Data were validated using quantitative PCR and Hyperion imaging mass cytometry. Comparative bioinformatic analyses revealed close similarities in NF2-related schwannomatosis and sporadic vestibular schwannoma tumours across the three datasets. Significant inflammatory markers and signalling pathways were closely matched in NF2-related schwannomatosis and sporadic vestibular schwannoma, relating to the proliferation of macrophages, angiogenesis and inflammation. Bulk transcriptomic and imaging mass cytometry data identified macrophages as the most abundant immune population in vestibular schwannoma, comprising one-third of the cell mass in both NF2-related schwannomatosis and sporadic tumours. Importantly, there were no robust significant differences in signalling pathways, gene expression, cell type abundance or imaging mass cytometry staining between NF2-related schwannomatosis and sporadic vestibular schwannoma. These data indicate strong similarities in the tumour immune microenvironment of NF2-related schwannomatosis and sporadic vestibular schwannoma. Vestibular schwannoma are brain tumours found in NF2-related schwannomatosis patients and non-NF2-related schwannomatosis sporadic patients. Gregory et al. found strong similarities in the cell types, blood vessels, gene expression and inflammatory pathways of NF2-related schwannomatosis and sporadic vestibular schwannoma; thus, drugs and clinical trials may be equally effective in both groups.