Background: The application of immunotherapy for pediatric CNS malignancies has been limited by the poorly understood immune landscape in this context. The aim of this study was to uncover the mechanisms of immune suppression common among pediatric brain tumors. Methods: We apply an immunologic clustering algorithm validated by The Cancer Genome Atlas Project to an independent pediatric CNS transcriptomic dataset. Within the clusters, the mechanisms of immunosuppression are explored via tumor microenvironment deconvolution and survival analyses to identify relevant immunosuppressive genes with translational relevance. Results: High-grade diseases fall predominantly within an immunosuppressive subtype (C4) that independently lowers overall survival time and where common immune checkpoints (e.g., PDL1, CTLA4) are less relevant. Instead, we identify several alternative immunomodulatory targets with relevance across histologic diseases. Specifically, we show how the mechanism of EZH2 inhibition to enhance tumor immunogenicity in vitro via the upregulation of MHC class 1 is applicable to a pediatric CNS oncologic context. Meanwhile, we identify that the C3 (inflammatory) immune subtype is more common in low-grade diseases and find that immune checkpoint inhibition may be an effective way to curb progression for this subset. Conclusions: Three predominant immunologic clusters are identified across pediatric brain tumors. Among high-risk diseases, the predominant immune cluster is associated with recurrent immunomodulatory genes that influence immune infiltrate, including a subset that impacts survival across histologies.
背景：免疫疗法在儿童中枢神经系统恶性肿瘤中的应用，因该领域免疫微环境认知不足而受限。本研究旨在揭示儿童脑肿瘤中普遍存在的免疫抑制机制。方法：我们将经癌症基因组图谱计划验证的免疫聚类算法应用于独立的儿童中枢神经系统转录组数据集。通过肿瘤微环境反卷积分析和生存分析，在各聚类中探索免疫抑制机制，以识别具有转化医学意义的相关免疫抑制基因。结果：高级别疾病主要集中于免疫抑制亚型（C4），该亚型独立降低总生存期，且常见免疫检查点（如PDL1、CTLA4）相关性较弱。相反，我们发现了多个跨组织学类型相关的替代性免疫调节靶点。具体而言，我们通过体外实验证明EZH2抑制剂通过上调MHC I类分子增强肿瘤免疫原性的机制，在儿童中枢神经系统肿瘤背景下具有适用性。同时，我们发现C3（炎症性）免疫亚型在低级别疾病中更为常见，并指出免疫检查点抑制可能是遏制该亚型疾病进展的有效途径。结论：我们在儿童脑肿瘤中识别出三种主要免疫聚类。在高危疾病中，主要免疫聚类与影响免疫浸润的复现性免疫调节基因相关，其中部分基因对跨组织学类型的生存期具有影响。
Revealing Pan-Histology Immunomodulatory Targets in Pediatric Central Nervous System Tumors
肿瘤(癌症)患者之家