Immu-03. Characterizing the Immune Microenvironment of Pediatric Brain Tumors

Abstract

Therapy for pediatric central nervous system (CNS) malignancies can be toxic, and outcomes are suboptimal. Immunotherapy holds promise as a therapeutic avenue, but one of the challenges in its application is the poorly understood microenvironment of pediatric CNS tumors. The Children’s Brain Tumor Network released the Pediatric Brain Tumor Atlas, containing the expression profile of nearly 700 primary CNS tumors. To study the immune microenvironment, a classification from The Cancer Genome Atlas project is applied. High-grade lesions are predominantly lymphocyte deplete (C4, 80%) or immunologically quiet (C5, 7.6%). Low-grade lesions are more mixed with 43% C4, 26% C5, and a higher proportion of inflammatory subtype (C3, 28%). For survival parameters, immune subtype and tumor grade are associated. Using a multivariate cox regression model, the hazard ratio is 2.2 (0.86 – 5.4, p = 0.102) and 3.6 (1.2 – 10.9, p = 0.02) for C4 and C5, respectively. Deconvolution of immune cell gene signatures provides insight into the phenotype of lymphocyte infiltrate, which averages 8.6% (IQR 5.4% – 9.8%) across all samples. For high-grade samples, greater than median expression of T cell-, monocyte-, macrophage-, and B cell-gene signatures are each associated with decreased survival (p < 0.05). Microglia gene signatures have decreased relative expression in high-grade samples compared to low-grade samples (p < 0.001). It is hypothesized that the expression of inhibitory immunomodulators contributes to a pro-tumorigenic microenvironment and represent potential therapeutic targets. In the absence of normal samples in the data set, differential gene expression experiments between disease states can reveal upregulated immunomodulators. Focusing on diffuse midline glioma, immunologic pathways are downregulated. Furthermore, 9 inhibitory immunomodulators, including KDM1A, EZH2, CD276, and VTCN1, are significantly expressed relative to midline low-grade glioma with equivalent immune subtype. Overall, our analysis contributes to the understanding of the immune microenvironment and mechanisms of immune escape for pediatric CNS malignancies.