Immunologic Profiling of Mutational and Transcriptional Subgroups in Pediatric and Adult High-Grade Gliomas
Immunologic Profiling of Mutational and Transcriptional Subgroups in Pediatric and Adult High-Grade Gliomas
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DOI：
10.1158/2326-6066.cir-18-0939
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发表时间：
2019-09-01
影响因子：
10.1
通讯作者：
Mohme, Malte
中科院分区：
文献类型：
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作者：
Bockmayr, Michael;Klauschen, Frederick;Mohme, Malte
高级别胶质瘤的免疫治疗策略正在研究中。确定相关的免疫途径是振兴肿瘤特异性免疫应答所必需的。因此，我们研究了高级别胶质瘤不同亚组的免疫表型，重点是儿科和青少年患者的罕见遗传亚组，以确定潜在的靶向机制。我们收集了1,135例高级别胶质瘤患者的已发表基因表达数据，并应用机器学习技术确定其转录（间充质，经典，神经和前神经）和突变[K27，G34，IDH和野生型（WT）]亚型。浸润性免疫细胞和功能性免疫途径的基因特征与组织学诊断、年龄、转录和突变亚组相关。我们的分析确定了四种不同的免疫细胞浸润微环境特征（免疫1-4），可以分为血管，单核细胞/基质，单核细胞/T细胞，和抗原呈递细胞（APC）/自然杀伤（NK）细胞/T细胞为主的免疫簇。免疫细胞表达谱与转录和突变亚组相关，但与年龄和组织学诊断无关。通过包括功能途径和相关的免疫刺激和抑制受体-配体相互作用的表达，我们能够定义免疫微环境，并确定可能的免疫亚型与预后不良。此外，将总生存期与免疫学景观和检查点分子进行比较，揭示了转录和突变亚组内的相关性，突出了PD-1/PD-L1检查点抑制在K27突变肿瘤中的潜在应用。我们的研究表明，转录和突变亚组的特征在于不同的免疫肿瘤微环境，证明了高级别胶质瘤中的免疫异质性，并建议对即将进行的免疫治疗试验进行免疫特异性分层。
Immunologic treatment strategies are under investigation for high-grade gliomas. Determining relevant immunologic pathways is required for invigorating a tumor-specific immune response. We therefore investigated the immunologic phenotypes within different subgroups of high-grade gliomas, with a focus on rare genetic subgroups of pediatric and adolescent patients to identify potentially targetable mechanisms. We gathered published gene-expression data from 1,135 high-grade glioma patients and applied a machine-learning technique to determine their transcriptional (mesenchymal, classic, neural, and proneural) and mutational [K27, G34, IDH, and wild type (WT)] subtypes. Gene signatures of infiltrating immune cells and functional immune pathways were evaluated in correlation to histologic diagnosis, age, and transcriptional and mutational subgroups. Our analysis identified four distinct microenvironmental signatures of immune cell infiltration (immune 1-4), which can be stratified into vascular, monocytic/stromal, monocytic/T-cell-, and antigen-presenting cell (APC)/natural killer (NK) cell/T-cell-dominated immune clusters. Immune cell expression profiles correlated with transcriptional and mutational subgroups but were independent of age and histologic diagnosis. By including functional pathways and correlating the expression of immunostimulatory and -inhibitory receptor-ligand interactions, we were able to define the immunologic microenvironment and identify possible immunologic subtypes associated with poor prognosis. In addition, comparison of overall survival with the immunologic landscape and with checkpoint molecules revealed correlations within the transcriptional and mutational subgroups, highlighting the potential application of PD-1/PD-L1 checkpoint inhibition in K27-mutated tumors. Our study shows that transcriptional and mutational subgroups are characterized by distinct immunologic tumor microenvironments, demonstrating the immunologic heterogeneity within high-grade gliomas and suggesting an immune-specific stratification for upcoming immunotherapy trials.