Joost Dejaegher1, Lien Solie1, Zoé Hunin1, Raf Sciot2, David Capper3,4, Christin Siewert5, Sofie Van Cauter6,7, Guido Wilms6, Johan van Loon1, Nadine Ectors8, Steffen Fieuws9, Stefan M Pfister10, Stefaan W Van Gool11, Steven De Vleeschouwer5. 1. Research Group Experimental Neurosurgery and Neuroanatomy, KU Leuven, Leuven, Belgium and Leuven Brain Institute, Leuven, Belgium. 2. Department of Pathology, University Hospitals Leuven, Leuven, Belgium. 3. Charité‒Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin; Berlin Institute of Health, Department of Neuropathology, Berlin, Germany. 4. German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany. 5. German Cancer Consortium, Partner Site Berlin, German Cancer Research Center, Heidelberg, Germany. 6. Department of Radiology, University Hospitals Leuven, Leuven, Belgium. 7. Department of Medical Imaging, Ziekenhuis Oost Limburg, Genk, Belgium. 8. Biobank, University Hospitals Leuven, Leuven, Belgium. 9. Interuniversity Center for Biostatistics and Statistical Bioinformatics, KU Leuven, University of Leuven and University of Hasselt, Leuven, Belgium. 10. Hopp Children's Cancer Center Heidelberg, German Cancer Research Center and German Cancer Consortium, and University Hospital Heidelberg, Heidelberg, Germany. 11. Immun-Onkologisches Zentrum Köln, Köln, Germany.
Abstract
BACKGROUND: Histologically classified glioblastomas (GBM) can have different clinical behavior and response to therapy, for which molecular subclassifications have been proposed. We evaluated the relationship of epigenetic GBM subgroups with immune cell infiltrations, systemic immune changes during radiochemotherapy, and clinical outcome. METHODS: 450K genome-wide DNA methylation was assessed on tumor tissue from 93 patients with newly diagnosed GBM, treated with standard radiochemotherapy and experimental immunotherapy. Tumor infiltration of T cells, myeloid cells, and Programmed cell death protein 1 (PD-1) expression were evaluated. Circulating immune cell populations and selected cytokines were assessed on blood samples taken before and after radiochemotherapy. RESULTS: Forty-two tumors had a mesenchymal, 27 a receptor tyrosine kinase (RTK) II, 17 RTK I, and 7 an isocitrate dehydrogenase (IDH) DNA methylation pattern. Mesenchymal tumors had the highest amount of tumor-infiltrating CD3+ and CD8+ T cells and IDH tumors the lowest. There were no significant differences for CD68+ cells, FoxP3+ cells, and PD-1 expression between groups. Systemically, there was a relative increase of CD8+ T cells and CD8+ PD-1 expression and a relative decrease of CD4+ T cells after radiochemotherapy in all subgroups except IDH tumors. Overall survival was the longest in the IDH group (median 36 mo), intermediate in RTK II tumors (27 mo), and significantly lower in mesenchymal and RTK I groups (15.5 and 16 mo, respectively). CONCLUSIONS: Methylation based stratification of GBM is related to T-cell infiltration and survival, with IDH and mesenchymal tumors representing both ends of a spectrum. DNA methylation profiles could be useful in stratifying patients for immunotherapy trials.
BACKGROUND: Histologically classified glioblastomas (GBM) can have different clinical behavior and response to therapy, for which molecular subclassifications have been proposed. We evaluated the relationship of epigenetic GBM subgroups with immune cell infiltrations, systemic immune changes during radiochemotherapy, and clinical outcome. METHODS: 450K genome-wide DNA methylation was assessed on tumor tissue from 93 patients with newly diagnosed GBM, treated with standard radiochemotherapy and experimental immunotherapy. Tumor infiltration of T cells, myeloid cells, and Programmed cell death protein 1 (PD-1) expression were evaluated. Circulating immune cell populations and selected cytokines were assessed on blood samples taken before and after radiochemotherapy. RESULTS: Forty-two tumors had a mesenchymal, 27 a receptor tyrosine kinase (RTK) II, 17 RTK I, and 7 an isocitrate dehydrogenase (IDH) DNA methylation pattern. Mesenchymal tumors had the highest amount of tumor-infiltrating CD3+ and CD8+ T cells and IDH tumors the lowest. There were no significant differences for CD68+ cells, FoxP3+ cells, and PD-1 expression between groups. Systemically, there was a relative increase of CD8+ T cells and CD8+ PD-1 expression and a relative decrease of CD4+ T cells after radiochemotherapy in all subgroups except IDH tumors. Overall survival was the longest in the IDH group (median 36 mo), intermediate in RTK II tumors (27 mo), and significantly lower in mesenchymal and RTK I groups (15.5 and 16 mo, respectively). CONCLUSIONS: Methylation based stratification of GBM is related to T-cell infiltration and survival, with IDH and mesenchymal tumors representing both ends of a spectrum. DNA methylation profiles could be useful in stratifying patients for immunotherapy trials.
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