Abstract
It is recognized that the tumor microenvironment (TME) plays a critical role in the biology of cancer. To better understand the role of immune cell components in CNS tumors, we applied a deconvolution approach to bulk DNA methylation array data in a large set of newly profiled samples (n = 741) as well as samples from external data sources (n = 3311) of methylation-defined glial and glioneuronal tumors. Using the cell-type proportion data as input, we used dimensionality reduction to visualize sample-wise patterns that emerge from the cell type proportion estimations. In IDH-wildtype glioblastomas (n = 2,072), we identified distinct tumor clusters based on immune cell proportion and demonstrated an association with oncogenic alterations such as EGFR amplification and CDKN2A/B homozygous deletion. We also investigated the immune cluster-specific distribution of four malignant cellular states (AC-like, OPC-like, MES-like and NPC-like) in the IDH-wildtype cohort. We identified two major immune-based subgroups of IDH-mutant gliomas, which largely aligned with 1p/19q co-deletion status. Non-codeleted gliomas showed distinct proportions of a key genomic aberration (CDKN2A/B loss) among immune cell-based groups. We also observed significant positive correlations between monocyte proportion and expression of PD-L1 and PD-L2 (R = 0.54 and 0.68, respectively). Overall, the findings highlight specific roles of the TME in biology and classification of CNS tumors, where specific immune cell admixtures correlate with tumor types and genomic alterations.
Highlights
Glial and glioneuronal tumors represent a wide range of tumor types with distinct biology and clinical outcomes and are currently assigned WHO grades 1–4 based on histopathologic and molecular features [1, 53]
Identification and verification of methylation‐derived immune cell populations A critical step in the deconvolution of bulk data is the appropriate choice of purified reference cell types and confirming a homogeneous population
This set consisted of seven methylation-defined glioma types: GBM-G34, GBM-MES, GBM-MID, GBM-MYCN, GBM-RTKI, GBM-RTKII and GBM-RTKIII that were defined using DKFZ DNA methylation classifier calibrated scores [10]
Summary
Glial and glioneuronal tumors represent a wide range of tumor types with distinct biology and clinical outcomes and are currently assigned WHO grades 1–4 based on histopathologic and molecular features [1, 53]. The tumor microenvironment (TME) is a critical element in glioma biology and has been shown to alter sensitivity to immune-based therapies [17, 86]. Distinct epigenetic profiles have been recognized in gliomas based on DNA methylation and, in combination with other somatic alterations, characterized clinically relevant subtypes: H3 K27, G34, IDH1, RTKI, RTKII, and mesenchymal [82]. IDH-wt subclass RTK III was predominantly reported in children and young adults, and correlates with pediatric high grade glioma, showing lower rates of TERT mutation and EGFR amplification as compared to adult-type GBMs [80]. DNA methylation profiling has emerged as a useful technique for tumor classification and the identification of novel subtypes in glial and glioneuronal tumors [10, 66]
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