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

Our plain-English summary of Analysis of DNA methylation patterns in the tumor immune microenvironment of metastatic melanoma, by S. Mitra, M. Lauss, R. Cabrita, et al (Molecular Oncology, 2020).

The study

• Authors: S. Mitra, M. Lauss, R. Cabrita, J. Choi, T. Zhang, K. Isaksson, H. Olsson, C. Ingvar, A. Carneiro, J. Staaf, M. Ringnér, K. Nielsen, K.M. Brown, G. Jönsson
• Journal: Molecular Oncology
• Published: 2020;14(5):933-950
• Cited by: 41 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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 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.

© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

In plain English

This study did not examine asbestos. It analyzed tumor samples from people with metastatic melanoma, a skin cancer that had spread. The authors measured DNA methylation, a chemical marking on genes, at 67 sites linked to immune cell types. They studied 180 tumors from Skane University Hospital, Sweden, collected before modern immunotherapy and targeted drugs. The tumors fell into three groups. Cluster 1 had the lowest methylation and, on staining, the most immune-cell infiltration. Compared with Cluster 1, patients in Cluster 2 (hazard ratio 2.10, 95% confidence interval 1.22 to 3.64) and Cluster 3 (hazard ratio 2.18, 1.33 to 3.56) had a higher risk of dying from melanoma. The groups were found again in melanoma data from The Cancer Genome Atlas (TCGA), where Cluster 3 had worse overall survival than Cluster 1 (hazard ratio 2.29, 1.54 to 3.40). The authors also analyzed 15 other TCGA tumor types, including mesothelioma. Mesothelioma appears in the figures, but the text reports no result specific to it. The authors concluded that their results point toward immunotherapy tailored to each tumor's immune environment.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory analysis of DNA methylation in stored tumor samples from a historical patient group, with checks in public datasets (TCGA)
• Who was studied: 180 metastatic melanoma tumors (the Lund cohort) from the Department of Surgery at Skane University Hospital, Sweden, collected before immune checkpoint inhibitors and targeted therapies came into use. TCGA melanoma tumors and 15 other TCGA solid tumor cohorts were also analyzed.
• Exposure: No asbestos or fiber exposure was studied. The factor examined was tumor DNA methylation at 67 sites (CpGs) associated with immune cell types.
• Main results:
  • Melanoma-specific (disease-specific) survival in the Lund cohort, compared with Cluster 1: Cluster 2 HR 2.10 (95% CI 1.22–3.64; P = 0.008); Cluster 3 HR 2.18 (95% CI 1.33–3.56; P = 0.002)
  • Distant metastasis-free survival in the Lund cohort: Cluster 2 HR 2.45 (95% CI 1.30–4.61; P = 0.005) compared with Cluster 1
  • Among the 127 of 180 tumors with staining data, Cluster 1 had the highest percentage of samples with strong and localized infiltration of TILs, CD3+ and CD8+ T cells
  • Among the 129 of 180 tumors with mutation data, the clusters were not related to tumor mutational burden
  • Tumors with any PTEN alteration event were distributed differently across clusters (chi-square P < 0.001), and Cluster 3 showed the highest enrichment
  • In the TCGA melanoma cohort, Cluster 3 had worse overall survival than Cluster 1 (HR 2.29; 95% CI 1.54–3.40; P < 0.001)
  • Across the cancer types analyzed, most significant links between low immune methylation and good outcome occurred in only two tumor types: metastatic melanoma and head and neck squamous cell carcinoma
• The authors' conclusion: The authors concluded that their results point toward a more tailored approach to immunotherapy based on the tumor's immune microenvironment
• Limitations the authors state:
  • For the non-melanoma TCGA cohorts, the authors relaxed the criteria for selecting methylation sites, because some reference cell lines did not match the methylation pattern of most cell lines of their tumor type

Topics

Medical terms in this study, explained in our Lexicon: Tumor Microenvironment.

Related studies

• Wilms tumor 1/cytokeratin dual-color immunostaining reveals distinctive staining patterns in metastatic melanoma, metastatic carcinoma, and mesothelial cells in pleural fluids: an effective first-line test for the workup of malignant effusions — J.R. Conner, E.S. Cibas, et al. (2014)
• Metastatic Melanoma With Papillary Features: A Mimic and Possible Diagnostic Pitfall — A. Valero-Torres, V.G. Prieto, et al. (2017)
• Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non-Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors — S. Hendry, R. Salgado, et al. (2017)
• Ocular melanoma and the BAP1 hereditary cancer syndrome: implications for the dermatologist — L.M. Martorano, R.R. Winkelmann, et al. (2014)
• Molecular and Histopathological Characterization of the Tumor Immune Microenvironment in Advanced Stage of Malignant Pleural Mesothelioma — N.S. Patil, L. Righi, et al. (2018)
• Are macrophages, myeloid derived suppressor cells and neutrophils mediators of local suppression in healthy and cancerous tissues in aging hosts? — C. Jackaman, D.J. Nelson (2014)

Browse more research in Molecular Oncology, or return to medical research.