Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, F-75013 Paris, France. Equipe labellisée LNCC.
Department of Neurology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Curr Opin Oncol. 2022 Nov 1;34(6):653-660. doi: 10.1097/CCO.0000000000000895. Epub 2022 Aug 24.
Immunotherapeutic approaches have yet to demonstrate their clinical efficacy in diffuse gliomas. Evidence is mounting that the central nervous system is subject to immune surveillance, but brain tumours manage to escape due to factors intrinsic to their tumoral immune microenvironment (TME). This review aims to discuss the recently characterized molecular bases of the glioma TME and the potentially actionable targets to improve immunotherapeutic results in these hard-to-treat cancers.
Single-cell studies defined the composition of the glioma immune TME and its peculiarities compared with other solid cancers. In isocitrate dehydrogenase (IDH) wildtype gliomas, the TME is enriched in myeloid cells (monocyte-derived macrophages and resident microglia) with mainly immunosuppressive functions. Lymphocytes can infiltrate the glioma TME, but are exposed to multiple immunomodulating signals that render them in a state of deep exhaustion. IDH mutant gliomas produce the oncometabolite D-2-hydroxyglutarate with negative effects on leukocyte recruitment and function, resulting in the induction of an 'immune-desert' TME.
Several molecular pathways have been recently identified in the induction of an 'immune-hostile' microenvironment in diffuse gliomas, unravelling potential vulnerabilities to targeted immunotherapies.
目的综述：免疫疗法在弥漫性神经胶质瘤中的临床疗效尚未得到证实。越来越多的证据表明，中枢神经系统受到免疫监视，但由于肿瘤免疫微环境（TME）的内在因素，脑肿瘤得以逃避。本文旨在讨论最近描述的胶质瘤 TME 的分子基础，以及改善这些难治疗癌症的免疫治疗结果的潜在治疗靶点。
最近的发现：单细胞研究定义了胶质瘤免疫 TME 的组成及其与其他实体瘤的特点。在异柠檬酸脱氢酶（IDH）野生型胶质瘤中，TME 富含具有主要免疫抑制功能的髓样细胞（单核细胞衍生的巨噬细胞和固有小胶质细胞）。淋巴细胞可以浸润胶质瘤 TME，但暴露于多种免疫调节信号下，使其处于深度衰竭状态。IDH 突变型胶质瘤产生致癌代谢物 D-2-羟基戊二酸，对白细胞募集和功能有负面影响，导致“免疫荒漠”TME 的诱导。
总结：最近在弥漫性神经胶质瘤中诱导“免疫敌对”微环境的几个分子途径已被确定，为靶向免疫治疗揭示了潜在的弱点。
