Analysis of DNA methylation patterns in the tumor immune microenvironment of metastatic melanoma

Abstract

The presence of immune cells in the tumor microenvironment has been associated with response to immunotherapies across several cancer types, including melanoma. Despite its therapeutic relevance, characterization of the melanoma immune microenvironments remains insufficiently explored. To distinguish the immune microenvironment in a cohort of 180 metastatic melanoma clinical specimens, we developed a method using promoter CpG methylation of immune cell type-specific genes extracted from genome-wide methylation arrays. Unsupervised clustering identified three immune methylation clusters with varying levels of immune CpG methylation that are related to patient survival. Matching protein and gene expression data further corroborated the identified epigenetic characterization. Exploration of the possible immune exclusion mechanisms at play revealed likely dependency on MITF protein level and PTEN loss-of-function events for melanomas unresponsive to immunotherapies (immune-low). To understand whether melanoma tumors resemble other solid tumors in terms of immune methylation characteristics, we explored 15 different solid tumor cohorts from TCGA. Low-dimensional projection based on immune cell type-specific methylation revealed grouping of the solid tumors in line with melanoma immune methylation clusters rather than tumor types. Association of survival outcome with immune cell typespecific methylation differed across tumor and cell types. However, in melanomas immune cell type-specific methylation was associated with inferior patient survival. Exploration of the immune methylation patterns in a pan-cancer context suggested that specific immune microenvironments might occur across the cancer spectrum. Together, our findings underscore the existence of diverse immune microenvironments, which may be informative for future immunotherapeutic applications.

Data mining of immune-related prognostic genes in metastatic melanoma microenvironment

“…Top GO terms in the biological process included immune response, inflammatory response, signal transduction, innate immune response and adaptive immune response In addition, all the pathways that were yielded from KEGG analysis were associated with immune response. Consistent with previous studies, our findings verified that immune cells and extracellular matrix play significant roles in building the melanoma microenvironment [19][20][21]. Furthermore, we performed the overall survival analysis of 663 immune-related genes and identified that 600 genes (90.5%) were associated with better outcomes in metastatic melanoma patients.…”

DNA methylation-based prediction of response to immune checkpoint inhibition in metastatic melanoma

“…37 38 In contrast, Mitra et al investigated DNA methylation clusters based on median methylation values of selected immune cell-specific genes in melanoma patients but failed bringing forth an ICI response prediction signature. 25 The superior goal of a successful anticancer therapy is a long-term clinical benefit. Immunotherapy can lead to remarkable responses which can be objectified by imaging techniques.…”

“… 24 Moreover, immune cell methylation patterns might serve as prognostic biomarkers in melanoma. 25 Taken together, there is still a lack of reliable biomarkers for the prediction of a successful therapy response after ICI treatment. DNA methylation profiling might be a robust approach for the development of prognostic or even predictive biomarkers in cancer, as so far, there is still a lack of reliable biomarkers for the prediction of a successful therapy response after ICI treatment.…”

Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications

“…This process is catalyzed by DNA methyltransferase (DNMT) and uses S-adenosyl methionine (SAM) as the methyl group donor (90)(91)(92). In a pan-cancer context, Mitra et al explored and discovered varying levels of CpG methylation of immune celltype-specific genes that are related to patient survival (93). A comprehensive retrospective paper emphasized the importance of clarifying the DNA methylation sites for the development of cancer biomarkers (94).…”