Microglial immunosurveillance of oncogenic IDH – (CONVINCE-IDH)

• Applicant: Professor Dr. Michael Platten
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 500299701

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.

• DFG Programme: Priority Programmes
• Subproject of: SPP 2395: Local and peripheral drivers of microglial diversity and function