German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ).
Neurology Clinic Heidelberg, Heidelberg University Hospital.
Curr Opin Oncol. 2018 Nov;30(6):368-374. doi: 10.1097/CCO.0000000000000478.
The present review introduces recent progress in eliciting the role of mutant isocitrate dehydrogenase (IDH) in gliomas, especially regarding its mode of action as a modulator of antitumor immune response, and provides rationales for targeting mutant IDH in glioma immunotherapy. Both the development of small molecule inhibitors repressing the enzymatic activity of mutant IDH and novel, mechanism-led combination immunotherapies are discussed.
Since the discovery of highly frequent IDH mutations in low-grade gliomas and nonsolid malignancies, its tumor cell-intrinsic effects have been intensively investigated. Tumor cells expressing mutant IDH display profound alterations of redox control capacity, phospholipid profile, and ATP supply. Recent findings suggest that IDH mutations - via intricate, yet druggable pathways - cause immunological alterations, highlighting the importance of oncogenic drivers as modulators of antitumor immunity and targets for immunotherapy.
Mutant IDH is not only a disease-defining biomarker and oncogenic driver in glioma, but is also a neoantigen and a regulator of glioma immune evasion. Effective and specific strategies targeting the immunomodulatory properties of mutant IDH may complement current (immuno-)therapeutic strategies and approved antiglioma treatments to improve outcome.
本文介绍了近年来在揭示突变型异柠檬酸脱氢酶（IDH）在胶质瘤中的作用方面的进展，特别是其作为抗肿瘤免疫反应调节剂的作用模式，并为胶质瘤免疫治疗中靶向突变型 IDH 提供了依据。讨论了小分子抑制剂抑制突变型 IDH 酶活性的发展以及新的、基于机制的联合免疫疗法。
自低级别胶质瘤和非实体恶性肿瘤中发现高度频繁的 IDH 突变以来，其肿瘤细胞内在作用已被深入研究。表达突变型 IDH 的肿瘤细胞显示出氧化还原控制能力、磷脂谱和 ATP 供应的深刻改变。最近的研究结果表明，IDH 突变通过错综复杂但可药物治疗的途径导致免疫改变，强调了致癌驱动因素作为抗肿瘤免疫调节剂和免疫治疗靶点的重要性。
突变型 IDH 不仅是胶质瘤中具有定义疾病特征的生物标志物和致癌驱动因素，也是新抗原和胶质瘤免疫逃逸的调节剂。针对突变型 IDH 的免疫调节特性的有效和特异性策略可能补充当前（免疫）治疗策略和批准的抗胶质瘤治疗方法，以改善预后。
