DIMEimmune: Robust estimation of infiltrating lymphocytes in CNS tumors from DNA methylation profiles

Abstract

The interaction of CNS tumors with infiltrating lymphocytes plays an important role in their initiation and progression and might be related to therapeutic responses. Gene expression-based methods have been successfully used to characterize the tumor microenvironment. However, methylation data are now increasingly used for molecular diagnostics and there are currently only few methods to infer information about the microenvironment from this data type. Using an approach based on differential methylation and principal component analysis, we developed DIMEimmune (Differential Methylation Analysis for Immune Cell Estimation) to estimate CD4 + and CD8 + T cell abundance as well as tumor-infiltrating lymphocytes (TILs) scores from bulk methylation data. Well-established approaches based on gene expression data and immunohistochemistry-based lymphocyte counts were used as benchmarks. The comparison of DIMEimmune to the previously published MethylCIBERSORT and MeTIL algorithms showed an improved correlation with both gene expression-based and immunohistological results across different brain tumor types. Further, we applied our method to large datasets of glioma, medulloblastoma, atypical teratoid/rhabdoid tumors (ATRTs) and ependymoma. High-grade gliomas showed higher scores of tumor-infiltrating lymphocytes than lower-grade gliomas. There were overall only few tumorinfiltrating lymphocytes in medulloblastoma subgroups. ATRTs were highly infiltrated by lymphocytes, most prominently in the MYC subgroup. DIMEimmune-based estimates of TILs were a significant prognostic factor in the overall cohort of gliomas and medulloblastomas, but not within methylation-based diagnostic subgroups. To conclude, DIMEimmune allows for robust estimates of TIL abundance and might contribute to establishing them as a prognostic or predictive factor in future studies of CNS tumors.

Molecular profile reveals immune-associated markers of medulloblastoma for different subtypes

“…This phenomenon implies that estimating the TILs and endothelial cells can contribute to identifying the progression and prognosis of MB. A previous study showed that the DIME (Differential Methylation Analysis for immune Cell Estimation)-TIL score was a negative prognostic factor in MB ( 42 ), which laterally supported our hypothesis. Furthermore, tumor endothelial cells are required for tumor angiogenesis, which is crucial for tumor progression and metastasis ( 43 ).…”

Recurrent posterior fossa group A (PFA) ependymoma in a young child with constitutional mismatch repair deficiency (CMMRD)

“…(I) Evaluation of the tumour microenvironment using immunohistochemistry showed focal clusters of CD8 (+) T cells both at diagnosis and relapse. (J) Estimates of CD8 infiltration using the DIME score using methylation data as described by Safaei et al [ 22 ] showed higher CD8 T‐cell scores for the index patient as compared with MMR‐proficient ependymomas ( p = 0.0087; Mann–Whitney test).…”

The Growing Relevance of Immunoregulation in Pediatric Brain Tumors

“…Algorithm like ESTIMATE, CIBERSORT or Microenvironment Cell Populations (MCP)-counter quantify immune and stromal cell populations based on defined marker gene expression signatures [ 55 , 56 , 57 ]. Further progress on deconvolution approaches was made on genome-wide DNA methylation data, introducing MeTIL, MethylCIBERSORT and DIMEimmune [ 58 , 59 , 60 ].…”

“…Lastly, significant prognostic relationships were found in infant SHH-MB (B cell amount significantly greater), low-risk Gr.3-MB (Treg significantly associated with poor survival) and pediatric HGG (monocytes significantly enriched in tumors with MAPK mutations) [ 21 ]. Safaei et al [ 60 ] developed DIMEimmune for differential methylation analysis for immune cell estimation [ 60 ]. This study calculated estimations of CD4+, CD8+ and tumor-infiltrating lymphocytes (TILs) for glioma, MB, ATRT and EPN methylation data.…”

“…ATRT were highly infiltrated by lymphocytes, most prominently in the MYC subgroup, while there were overall only a few TILs in MB subgroups. Among EPN, PFA-EPN had the largest estimated number of TILs [ 60 ].…”