T cell clones driving the intrinsic tumor-specific immune response in glioblastoma: identifying key players for immunotherapy

• Applicant: Privatdozent Dr. Malte Mohme
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 515049954

The current era of oncological treatment is being redefined by immunotherapeutic approaches. Employing and enhancing the immune system’s ability to target cancer cells has been the major focus of translational oncology over the past years. T cells represent the effector arm of the adaptive tumor-specific immune response, and they are able to track and eliminate tumor cells with unmatched specificity. However, the effects of T cell-driven immunotherapy have not yet reached their full potential in glioblastoma, as the mechanisms of cancer immune escape and local immunosuppression are hindering the execution of efficient immune-mediated cancer elimination by T cells. Clinical studies with checkpoint inhibitors have shown that the sole peripheral disinhibition of the intrinsic T cell response is not sufficient to counteract tumor recurrence and an additional enhancement of the tumor-specific cellular response is needed. Chimeric antigen receptor (CAR) T cells have been proposed to facilitate this targeted approach. However, one potential drawback of the CAR T cell approach is, that the continuously changing temporo-spatial heterogeneity of the glioblastoma molecular makeup poses a major challenge in terms of antigen definition and adaptation. We hypothesize, that the natural T cell response in glioblastoma may overcome this obstacle and that an intrinsic T cell response with the propensity to effectively select for tumor-specific target antigens can be identified. We believe that the proposed project is able to isolate shared T cell specificities in glioblastoma which can drive the tumor-specific immune response more efficiently than CAR T cells. We will use high-throughput T cell receptor sequencing (TCRseq) and bioinformatic antigen motif modeling to identify potentially common tumor-specific T cell clones, i.e. “T cell clones that matter in glioblastoma”, in diverse patient subgroups with favorable outcome and subsequentially perform single cell isolation of promising T cell clones. Cloning of T cells will be assisted by adapting the cloning and expansion strategy according to the results of a phenotypic characterization of tumor-infiltrating T lymphocytes. Taken together, our goal is to understand the basic biology of GBM-specific T cell responses and identify, characterize and isolate T cell clones which are able to effectively drive the tumor-specific immune response in glioblastoma. Our study will lay the basis for a better understanding of cell-based therapeutic treatment approaches in glioblastoma.

• DFG Programme: Research Grants
• Co-Investigator: Professorin Dr. Katrin Lamszus