Microglial immunosurveillance of oncogenic IDH – (CONVINCE-IDH)

异柠檬酸脱氢酶(IDH)突变的胶质瘤是一种无法治愈、生长缓慢的肿瘤，不可避免地会随着时间的推移而进展和恶性转化。早期实验性和低级别人IDH突变肿瘤已被证明以小胶质细胞为主，表明这种细胞类型在控制或促进IDH依赖的胶质瘤形成中发挥重要作用。与实验性IDH野生型肿瘤相关的小胶质细胞相比，突变的IDH相关小胶质细胞表现为肿瘤内的稳定表型，其趋化和抗原呈递能力降低。为了破译1)早期免疫逃避小胶质细胞监视的机制和2)小胶质细胞致病细胞与其他细胞类型的连续串扰，驱动IDH依赖的胶质瘤形成，我们将利用复杂的遗传小鼠模型和WHO 2-4 IDH突变组织队列，并应用单细胞转录、表观遗传学和空间图谱。此外，作为早期和晚期IDH突变胶质瘤的替代物，样本内小胶质细胞多样性将在有或没有对比度增强区域的胶质瘤中进行评估。从机制上理解小胶质细胞的监视失败将有助于开发新的分子导向治疗方法，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.