Translational multimodality imaging of glioma hallmarks to assess the dynamics of the immune cell landscape and tumor cell invasion during targeted therapy

• Applicant: Professor Michael Breckwoldt, Ph.D.
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 460276399

Immunological processes play pivotal role in a variety of neurological diseases, including neoplastic conditions. Gliomas are highly malignant brain tumors which actively suppress anti-tumor immune responses. Another hallmark of glioma is their infiltrative nature into the adjacent parenchyma and to the contralateral hemisphere. Magnetic resonance imaging (MRI) is the main modality for initial diagnosis and treatment monitoring for many neurological disorders including glioma. However, visualizing the immunological cellular origins and thus the catalysts of disease is not possible in clinical practice. Clinical imaging is mainly restricted to assess morphological information (e.g. tumor size, extent of edema and gliosis) but does not provide “functional” information on immune cell influx, cellular distributions and perturbations that occur after therapy induction and which mediate treatment. This, however, would be crucial to better understand and eventually treat neurological disorders associated with innate and adaptive immune responses. Furthermore, novel therapies that modulate the tumor microenvironment (TME) and tumor cell invasion are entering clinical practice and require advanced treatment monitoring – an unmet clinical need for all solid cancer entities. Advanced imaging of inflammatory processes can also foster mechanistic insights into disease mechanisms and facilitate therapy development. Visualizing immune responses by direct tracking of effector cells could facilitate preclinical therapy development and allow treatment monitoring and patient stratification. Despite a number of proof of principle studies, the concept of immuno-imaging has not yet entered clinical practice. Major limitations of MRI include the resolution (~50µm to 1mm) and lack of specificity of conventional MR sequences. Optical imaging can overcome both limitations. Recent developments of tissue clearing and light sheet microscopy (“ultramicroscopy”, UM) allow the generation of 3D datasets at single cell resolution which can constitute a “ground truth” for MRI biomarker development. The main objectives of the proposal are to:1. Develop multimodality imaging to visualize innate and adaptive immune responses by MRI and correlative optical methods and “radiomic” post-processing tools for comprehensive image quantification.2. Assess different treatment paradigms (immunotherapy, irradiation) to develop a mechanistic understanding of innate and adaptive immune responses during therapy and infer imaging response markers.3. Develop MRI and correlated ultramicroscopy to visualize tumor cell infiltration for monitoring anti-invasive therapy.4. Translate imaging biomarkers to the human disease for monitoring immunotherapy and tumor cell infiltration in selected glioma cohorts.

• DFG Programme: Independent Junior Research Groups