Abstract
Immune-therapy is an attractive alternative therapeutic approach for targeting central nervous system (CNS) tumors and the constituency of the Tumor Immune Microenvironment (TIME) likely to predict patient response. Here, we describe the TIME of >6000 primarily pediatric CNS tumors using a deconvolution approach (methylCIBERSORT). We produce and validate a custom reference signature defining 11 non-cancer cell types to estimate relative proportions of infiltration in a panCNS tumor cohort spanning 80 subtypes. We group patients into three broad immune clusters associated with CNS tumor types/subtypes. In cohorts of medulloblastomas (n = 2325), malignant rhabdoid tumors (n = 229) and pediatric high-grade gliomas (n = 401), we show significant associations with molecular subgroups/subtypes, mutations, and prognosis. We further identify tumor-specific immune clusters with phenotypic characteristics relevant to immunotherapy response (i.e. Cytolytic score, PDL1 expression). Our analysis provides an indication of the potential future therapeutic and prognostic possibilities of immuno-methylomic profiling in pediatric CNS tumor patients that may ultimately inform approach to immune-therapy.
Highlights
Immune-therapy is an attractive alternative therapeutic approach for targeting central nervous system (CNS) tumors and the constituency of the Tumor Immune Microenvironment (TIME) likely to predict patient response
Where cancer represents relevant cancer cell line profiles from multiple tumor types, we verified the following: (i) that specific differentially methylated CpGs were captured for each cell type, (ii) the absence of batch effects following processing; and (iii) the CpGs selected were not confounded by being specific to any particular CNS cancer type (Fig. 1a, b and Supplementary Fig. 1)
We find diversity in TIME composition across these CNS tumors and demonstrate significant associations variously with tumor type, subtype, stage, grade, location, mutation, and survival
Summary
Immune-therapy is an attractive alternative therapeutic approach for targeting central nervous system (CNS) tumors and the constituency of the Tumor Immune Microenvironment (TIME) likely to predict patient response. Our analysis provides an indication of the potential future therapeutic and prognostic possibilities of immuno-methylomic profiling in pediatric CNS tumor patients that may inform approach to immune-therapy. Comparative studies between responders and non-responders indicate that multiple factors, including pre-existing T-cell infiltration, checkpoint molecule expression within the tumor, and mutational burden with consequent production of neoantigens correlate with response to immune therapy. Colorectal cancer of the molecular subtype CMS1 are characterized by DNA mismatch-repair defects, microsatellite instability, and hypermutation with accompanying infiltration of CD8+ T-cells[15] and expression of immune checkpoint proteins CTLA-4, PD-1, PDL1, and IDO116–18. Childhood brain tumors are thought to be relatively immunologically “cold” due to paucity of mutations (i.e., generally lacking neoantigens[20])
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