Microglial immunosurveillance of oncogenic isocitrate dehydrogenase (CONVINCE-IDH)

Malignant gliomas represent an enormous challenge in clinical oncology. Prognosis of patients with high-grade gliomas is poor despite modern surgery and radiochemotherapy. Effective immunotherapy is compromised by lack of well-characterized glioma-specific antigens and glioma-associated systemic and microenvironmental immunosuppression. The glioma microenvironment orchestrates tumor progression and resistance to therapy (Friedrich et al., Nature Cancer, 2021). Microglia and monocyte-derived macrophages (MDM) are significant regulators of the glioma microenvironment.
Current concepts propose a glioma microenvironment in which phenotypic and functional shaping of resident microglia and MDM depends on the tumor genotype, such as disease-defining mutations in the isocitrate dehydrogenase (IDH) gene (Platten et al., Nature, 2021). Functionally altered microglia and MDM in turn promote tumor growth by a variety of mechanisms, such as poor antigen presentation capacity and acquisition of an immunosuppressive phenotype. Temporal microglia-specific functional states within the truly mutant IDH-driven glioma microenvironment have not been defined yet.
IDH-mutant gliomas are slow-growing tumors that inevitably progress and transform over time. Early experimental and low grade human IDH-mutant tumors suggest an important role of microglia in controlling IDH-dependent gliomagenesis (Bunse et al., Nature Medicine, 2018). 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.

In this project, we aim to unravel mechanisms of surveillance failure by microglia in IDH-mutant gliomas. Specifically, we want to
A) decipher mechanisms of early immune escape from microglial surveillance and
B) identify consecutive microglial pathogenic cellular crosstalk to other cell types driving IDH-mutant-dependent gliomagenesis.

We will use 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, microglia diversity will be assessed in gliomas.

The results will help to develop molecularly-guided therapies preventing malignant transformation of IDH-mutant gliomas.