Mirco Friedrich1,2,3, Markus Hahn1,4, Julius Michel1,4, Roman Sankowski5, Michael Kilian1,4, Niklas Kehl1,4, Manina Günter6, Theresa Bunse1,4, Stefan Pusch7,8, Andreas von Deimling7,8, Wolfgang Wick9,10, Stella E Autenrieth6, Marco Prinz5, Michael Platten1,4,11,12, Lukas Bunse1,4. 1. DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 2. Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany. 3. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. 4. Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 5. Department of Neuropathology, Freiburg University Hospital, Freiburg, Germany. 6. Dendritic Cells in Infection and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. 7. Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany. 8. DKTK Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 9. Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany. 10. DKTK Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 11. Helmholtz Institute of Translational Oncology (HI-TRON), Mainz, Germany. 12. Immune Monitoring Unit, National Center for Tumor Diseases (NCT), Heidelberg, Germany.
Abstract
BACKGROUND: Dendritic cells (DC), the most potent professional antigen presenting cells capable of effective cross-presentation, have been demonstrated to license T helper cells to induce anti-tumor immunity in solid tumors. Specific DC subtypes are recruited to the injured brain by microglial chemokines, locally adapting to distinct transcriptional profiles. In isocitrate dehydrogenase type 1 (IDH) mutant gliomas, monocyte-derived macrophages have recently been shown to display an attenuated intratumoral antigen presentation capacity as consequence of the local accumulation of the oncometabolite R-2-hydroxyglutarate. The functionality and the contribution of DC to the IDH-mutant tumor microenvironment (TME) remains unclear. METHODS: Frequencies and intratumoral phenotypes of human DC in IDH-wildtype and -mutant high-grade gliomas are comparatively assessed by transcriptomic and proteomic profiling. DC functionality is investigated in experimental murine glioblastomas expressing the model antigen ovalbumin. Single-cell sequencing-based pseudotime analyses and spectral flow cytometric analyses are used to profile DC states longitudinally. RESULTS: DC are present in primary and recurrent high-grade gliomas and interact with other immune cell types within the TME. In murine glioblastomas, we find an IDH-status-associated major histocompatibility class I-restricted cross-presentation of tumor antigens by DC specifically in the tumor but not in meninges or secondary lymphoid organs of tumor-bearing animals. In single-cell sequencing-based pseudotime and longitudinal spectral flow cytometric analyses, we demonstrate an IDH-status-dependent differential, exclusively microenvironmental education of DC. CONCLUSION: Glioma-associated DCs are relevantly abundant in human IDH wildtype and mutant tumors. Glioma IDH mutations result in specifically educated, dysfunctional DCs via paracrine reprogramming of infiltrating monocytes, providing the basis for combinatorial immunotherapy concepts against IDH mutant gliomas.
BACKGROUND: Dendritic cells (DC), the most potent professional antigen presenting cells capable of effective cross-presentation, have been demonstrated to license T helper cells to induce anti-tumor immunity in solid tumors. Specific DC subtypes are recruited to the injured brain by microglial chemokines, locally adapting to distinct transcriptional profiles. In isocitrate dehydrogenase type 1 (IDH) mutant gliomas, monocyte-derived macrophages have recently been shown to display an attenuated intratumoral antigen presentation capacity as consequence of the local accumulation of the oncometabolite R-2-hydroxyglutarate. The functionality and the contribution of DC to the IDH-mutant tumor microenvironment (TME) remains unclear. METHODS: Frequencies and intratumoral phenotypes of human DC in IDH-wildtype and -mutant high-grade gliomas are comparatively assessed by transcriptomic and proteomic profiling. DC functionality is investigated in experimental murine glioblastomas expressing the model antigen ovalbumin. Single-cell sequencing-based pseudotime analyses and spectral flow cytometric analyses are used to profile DC states longitudinally. RESULTS: DC are present in primary and recurrent high-grade gliomas and interact with other immune cell types within the TME. In murine glioblastomas, we find an IDH-status-associated major histocompatibility class I-restricted cross-presentation of tumor antigens by DC specifically in the tumor but not in meninges or secondary lymphoid organs of tumor-bearing animals. In single-cell sequencing-based pseudotime and longitudinal spectral flow cytometric analyses, we demonstrate an IDH-status-dependent differential, exclusively microenvironmental education of DC. CONCLUSION: Glioma-associated DCs are relevantly abundant in human IDH wildtype and mutant tumors. Glioma IDH mutations result in specifically educated, dysfunctional DCs via paracrine reprogramming of infiltrating monocytes, providing the basis for combinatorial immunotherapy concepts against IDH mutant gliomas.