Single-cell analysis in diffuse gliomas in response to immune checkpoint inhibitors

• Applicant: Dr. Simon Gritsch
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Hematology, Oncology ; Rheumatology
• Term: from 2017 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 397978610

Diffuse gliomas are the most common primary brain tumors. In the absence of approved targeted therapies for these incurable, invariably fatal malignancies there is a tremendous medical need for new therapeutic concepts. Selective immunological targeting of glioma cells would be an optimal treatment. Recently, there has been remarkable clinical success of immunostimulatory approaches that block T-cell suppressive pathways (immune checkpoint inhibitors) in several tumor entities. However, immunotherapeutic approaches are still lacking efficacy in gliomas in part due to an incomplete understanding of glioma-immune interaction and the tumor microenvironment as well as poor definition of tumor-specific antigens for targeted immunotherapies. Here I propose to leverage single-cell RNA-sequencing to characterize in depth (1) T-cell programs and the tumor microenvironment in gliomas at diagnosis (2) the response of gliomas and the tumor microenvironment to immune checkpoint blockade in ongoing clinical trials. Single-cell transcriptomic methods enable the characterization of myeloid and lymphocyte transcriptional programs coupled to the reconstruction of T-cell receptor sequences, thus revealing both the clonality and the activity of immune cells directly in patients. Single-cell RNA-sequencing will also be used to assess transcriptional programs of malignant cells, infer partial genetic information and characterize how defined subpopulations of glioma cells are affected by therapies. This research project will pave the way for the development of effective immunotherapies in diffuse gliomas.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Mario Suvà, Ph.D.