PATH-53. IMMUNOLOGICAL PROFILING OF MUTATIONAL AND TRANSCRIPTIONAL SUBGROUPS IN PEDIATRIC AND ADULT HIGH-GRADE GLIOMAS

摘要

Immunological treatment strategies, including checkpoint inhibition, are currently under investigation for high-grade gliomas, but their success is limited. Hence, it is crucial to determine immunological pathways that can be targeted and to identify subgroups of patients likely to benefit from immunotherapies. Previous studies are still limited by comparably small sample sizes and there is only few data about specific immunological mechanisms in pediatric high-grade glioma. We gathered published gene expression data from 1135 adult and pediatric high-grade gliomas and applied a machine learning technique to determine their mutational (K27, G34, IDHmut, IDHwt) and transcriptional subtype. Subsequently, immune cell infiltration and functional immune pathway signatures were evaluated in correlation to histological diagnosis, age, transcriptional and mutational subtype. T-SNE analysis and unsupervised hierarchical clustering was applied to detect subgroup-specific immune microenvironments across all high-grade glioma subtypes. Four distinct microenvironmental phenotypes of immune cell infiltration were identified, which can be stratified into vascular, monocytic/stromal, monocytic/T-cell and APC/NK/T-cell dominant immune clusters. Immune cell infiltration correlated strongly with transcriptional and mutational subtypes but was independent of age and histological diagnosis (p< 0.01). H3F3A mutated tumors had significantly fewer tumor infiltrating lymphocytes and macrophages. By including functional pathways and correlating the expression of immunostimulatory and inhibitory receptor/ligand interactions, we were able to define the immunological microenvironment and to identify possible immunological subtypes associated with poor prognosis as well as subtypes that might be especially amenable to checkpoint inhibition. In addition, comparisons of overall survival with the immunological microenvironment and specifically with immune checkpoint molecules revealed diverse correlations within the transcriptional and mutational subgroups. In conclusion, we shat that mutational and transcriptional subgroups of pediatric and adult high-grade gliomas are characterized by distinct immunological tumor microenvironments. Our analysis demonstrates the immunological heterogeneity within this entity and emphasizes an immune specific stratification of subgroups for upcoming immunotherapy trials.