Immunologic Profiling of Mutational and Transcriptional Subgroups in Pediatric and Adult High-Grade Gliomas

TY - JOUR

T1 - Immunologic Profiling of Mutational and Transcriptional Subgroups in Pediatric and Adult High-Grade Gliomas

AU - Bockmayr, Michael

AU - Klauschen, Frederick

AU - Maire, Cecile L

AU - Rutkowski, Stefan

AU - Westphal, Manfred

AU - Lamszus, Katrin

AU - Schüller, Ulrich

AU - Mohme, Malte

N1 - Copyright ©2019, American Association for Cancer Research.

PY - 2019/9

Y1 - 2019/9

N2 - Immunologic treatment strategies are under investigation for high-grade gliomas. Determining relevant immunologic pathways is required for invigorating a tumor-specific immune response. We therefore investigated the immunologic phenotypes within different subgroups of high-grade gliomas, with a focus on rare genetic subgroups of pediatric and adolescent patients to identify potentially targetable mechanisms. We gathered published gene-expression data from 1,135 high-grade glioma patients and applied a machine-learning technique to determine their transcriptional (mesenchymal, classic, neural, and proneural) and mutational [K27, G34, IDH, and wild type (WT)] subtypes. Gene signatures of infiltrating immune cells and functional immune pathways were evaluated in correlation to histologic diagnosis, age, and transcriptional and mutational subgroups. Our analysis identified four distinct microenvironmental signatures of immune cell infiltration (immune 1-4), which can be stratified into vascular, monocytic/stromal, monocytic/T-cell-, and antigen-presenting cell (APC)/natural killer (NK) cell/T-cell-dominated immune clusters. Immune cell expression profiles correlated with transcriptional and mutational subgroups but were independent of age and histologic diagnosis. By including functional pathways and correlating the expression of immunostimulatory and -inhibitory receptor-ligand interactions, we were able to define the immunologic microenvironment and identify possible immunologic subtypes associated with poor prognosis. In addition, comparison of overall survival with the immunologic landscape and with checkpoint molecules revealed correlations within the transcriptional and mutational subgroups, highlighting the potential application of PD-1/PD-L1 checkpoint inhibition in K27-mutated tumors. Our study shows that transcriptional and mutational subgroups are characterized by distinct immunologic tumor microenvironments, demonstrating the immunologic heterogeneity within high-grade gliomas and suggesting an immune-specific stratification for upcoming immunotherapy trials.

AB - Immunologic treatment strategies are under investigation for high-grade gliomas. Determining relevant immunologic pathways is required for invigorating a tumor-specific immune response. We therefore investigated the immunologic phenotypes within different subgroups of high-grade gliomas, with a focus on rare genetic subgroups of pediatric and adolescent patients to identify potentially targetable mechanisms. We gathered published gene-expression data from 1,135 high-grade glioma patients and applied a machine-learning technique to determine their transcriptional (mesenchymal, classic, neural, and proneural) and mutational [K27, G34, IDH, and wild type (WT)] subtypes. Gene signatures of infiltrating immune cells and functional immune pathways were evaluated in correlation to histologic diagnosis, age, and transcriptional and mutational subgroups. Our analysis identified four distinct microenvironmental signatures of immune cell infiltration (immune 1-4), which can be stratified into vascular, monocytic/stromal, monocytic/T-cell-, and antigen-presenting cell (APC)/natural killer (NK) cell/T-cell-dominated immune clusters. Immune cell expression profiles correlated with transcriptional and mutational subgroups but were independent of age and histologic diagnosis. By including functional pathways and correlating the expression of immunostimulatory and -inhibitory receptor-ligand interactions, we were able to define the immunologic microenvironment and identify possible immunologic subtypes associated with poor prognosis. In addition, comparison of overall survival with the immunologic landscape and with checkpoint molecules revealed correlations within the transcriptional and mutational subgroups, highlighting the potential application of PD-1/PD-L1 checkpoint inhibition in K27-mutated tumors. Our study shows that transcriptional and mutational subgroups are characterized by distinct immunologic tumor microenvironments, demonstrating the immunologic heterogeneity within high-grade gliomas and suggesting an immune-specific stratification for upcoming immunotherapy trials.

U2 - 10.1158/2326-6066.CIR-18-0939

DO - 10.1158/2326-6066.CIR-18-0939

M3 - SCORING: Journal article

C2 - 31266783

VL - 7

SP - 1401

EP - 1411

JO - CANCER IMMUNOL RES

JF - CANCER IMMUNOL RES

SN - 2326-6066

IS - 9

ER -