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

Research output: Contribution to journalArticle

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 if 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 type-specific 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.

Details

Authors
Organisations
External organisations
  • National Cancer Institute, USA
  • Skåne University Hospital
  • National Bioinformatics Infrastructure Sweden (NBIS), SciLifeLab
  • Helsingborg Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
  • Dermatology and Venereal Diseases
Original languageEnglish
Pages (from-to)933-950
Number of pages18
JournalMolecular Oncology
Volume14
Issue number5
Early online date2020 Mar 9
Publication statusPublished - 2020 May
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

This article is protected by copyright. All rights reserved.

Related research output

Shamik Mitra, 2020, Lund: Lund University, Faculty of Medicine. 92 p.

Research output: ThesisDoctoral Thesis (compilation)

Rita Cabrita, 2020, Lund: Lund University, Faculty of Medicine. 86 p.

Research output: ThesisDoctoral Thesis (compilation)

View all (2)

Related projects

Kari Nielsen, Christian Ingvar, Göran B Jönsson, Håkan Olsson Dödsbo, Irina Baranovskaya, Anna Hafström, Katja Harbst, Iva Johansson, Åsa Ingvar, Johan Kappelin, Fredrik Johansson, Karolin Isaksson, Gustav Christensen & Ana Carneiro

2013/01/01 → …

Project: ResearchClinical research

View all (1)