Microglial immunosurveillance of oncogenic IDH – (CONVINCE-IDH)

异柠檬酸脱氢酶（IDH）突变胶质瘤是无法治愈的缓慢生长的肿瘤，不可避免的进展和恶性转化随着时间的推移。早期实验和低级别人idh突变肿瘤已被证明是由小胶质细胞主导的，这表明这种细胞类型在控制或促进idh依赖性胶质瘤形成中起重要作用。与实验性idh野生型肿瘤相关的小胶质细胞相比，突变型idh相关的小胶质细胞表现出瘤内稳态表型，其趋化和抗原递呈能力降低。为了破译i)早期免疫逃避小胶质细胞监视的机制和ii)连续的小胶质致病细胞串音到其他细胞类型，驱动idh依赖性胶质瘤形成，我们将利用复杂的遗传小鼠模型和WHO 2-4级idh突变组织队列，并应用单细胞转录组学，表观遗传学和空间分析。此外，作为早期和晚期idh突变胶质瘤的替代品，样本内小胶质细胞多样性将在有或没有对比增强区域的胶质瘤中进行评估。了解小胶质细胞监测失败的机制将有助于开发新的分子指导疗法，防止idh突变胶质瘤的恶性转化。

Isocitrate dehydrogenase (IDH)-mutant gliomas are incurable slow-growing tumors that inevitably progress and malignantly transform over time. Early experimental and low grade human IDH-mutant tumors have been shown to be dominated by microglial cells, suggesting an important role for this cell type in controlling or promoting IDH-dependent gliomagenesis. In comparison to microglia associated with experimental IDH-wildtype tumors, mutant IDH-associated microglia display an intratumoral steady state phenotype with reduced chemotactic and antigen presentation capacity. To decipher i) mechanisms of early immune escape from microglial surveillance and ii) consecutive microglial pathogenic cellular crosstalk to other cell types, driving IDH-dependent gliomagenesis, we will make use of complex genetic mouse models and WHO grade 2-4 IDH-mutant tissue cohorts, and apply single-cell transcriptomic, epigenetic and spatial profiling. In addition, as surrogate for early and late IDH-mutant gliomas, intrasample microglia diversity will be assessed in gliomas with or without contrast-enhancing regions. Mechanistic understanding of surveillance failure by microglia will help to develop novel molecularly-guided therapies preventing malignant transformation of IDH-mutant gliomas.