Prof. Dr. med. Michael Platten

Brain MRI scan of mice with brain tumors, that catabolize tryptophan (+ TDO) compared with tumors that do not catabolize tryptophan (- TDO) and do not form large tumors. Activation of the immunosuppressive AHR-program (TiPARP) in an immune cell (LCA) infiltrating a tryptophan catabolizing tumor.

The central nervous system (CNS) is an immune privileged organ with tightly regulated immune proceses. Regardless of this tight control autoimmunity takes place in the CNS. A paradigmatic autoimmune disease of the CNS is multiple sclerosis. On the other hand a hallmark of intrinsic CNS tumors is a profound systemic and local immunosuppression. The cellular and molecular mechanisms that are involved in the deregulation of CNS immunity in theses diseases are incompletely understood but probably involve pathways common to both, too much immune response in multiple sclerosis and too little immune response in brain tumors. Our group is interested in the metabolic control of CNS immunity and brain tumor development. The long-term goal is to identify crucial metabolic switches that may serve as therapeutic targets. In the past years we have identified key steps in the catabolism of the essential amino acid tryptophan as an endogenous mechanism, that restricts unwanted immune responses. These discoveries have led to the identification of novel therapeutic approaches and diagnostic tools that are currently undergoing clinical evaluation. Recently we have identified a key receptor of tryptophan catabolites that not only mediates tumor-promoting host cell interactions but also tumor cell intrinsic mechanisms to sustain tumor growth and invasiveness. These recent discoveries open a new view on the role of trptophan catabolism in cancer and identify novel therapeutic targets.

The discovery that TDO-derived tryptophan catabolites (kynurenines) drives brain and probably other types of cancer via the aryl hydrocarbon receptor (AHR) implied further question which will be tackled in the future. This is especially important as tryptophan catabolism has evolved in recent years as a key metabolic pathway in cancer biology and immune regulation and early clinical trials in cancer patients start employing pharmacological inhibitors. Future basic science projects will address (a) the regulation of tryptophan catabolism in cancer cells at the transcriptional and posttranscriptional level by host signals, (b) the role of tryptophan catabolism in stem cell maintainance, (c) the role of tryptophan catabolism in angiogenesis and (d) the role of tryptophan catabolism in autoimmune neuroinflammation. Future translational projects will deal with (e) the development of mesenchymal stem cell therapy for clinical application in patients with multiple sclerosis and (f) with the identification of drugs interfering with the AHR as potential therapeutics for malignant glioma targeting both, cell autonomous processes and tumor-associated immunosuppression. Finally we aim at implementing the first specific immunotherapy for patients with IDH1-mutated low-grade and anaplastic glioma.