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LAG3 (LAG-3, CD223) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma.

ABSTRACT: BACKGROUND:Lymphocyte activating 3 (LAG3, LAG-3, CD223) is a promising target for immune checkpoint inhibition in clear cell renal cell carcinoma (KIRC). The aim of this study was to investigate the epigenetic regulation of LAG3 in KIRC by methylation. METHODS:We correlated quantitative LAG3 methylation levels with transcriptional activity, immune cell infiltration, and overall survival in a cohort of n=533 patients with KIRC and n=160 normal adjacent tissue (NAT) samples obtained from The Cancer Genome Atlas (TCGA). Furthermore, we analyzed LAG3 methylation in peripheral blood mononuclear cells (PBMCs) and KIRC cell lines. We validated correlations between LAG3 expression, immune cell infiltrates, survival, and methylation in an independent KIRC cohort (University Hospital Bonn (UHB) cohort, n=118) by means of immunohistochemistry and quantitative methylation-specific PCR. RESULTS:We found differential methylation profiles among PBMCs, NAT, KIRC cell lines, and KIRC tumor tissue. Methylation strongly correlated with LAG3 mRNA expression in KIRCs (TCGA cohort) and KIRC cell lines. In the UHB cohort, methylation correlated with LAG3-positive immune cells and tumor-intrinsic LAG3 protein expression. Furthermore, LAG3 methylation strongly correlated with signatures of distinct immune cell infiltrates, an interferon-y signature (TCGA cohort), and immunohistochemically quantified CD45+, CD8+, and CD4+ immune?cell infiltrates (UHB cohort). LAG3 mRNA expression (TCGA cohort), methylation (both cohorts), and tumor cell-intrinsic protein expression (UHB cohort) was significantly associated with overall survival. CONCLUSION:Our data suggest an epigenetic regulation of LAG3 expression in tumor and immune cells via DNA methylation. LAG3 expression and methylation is associated with a subset of KIRCs showing a distinct clinical course and immunogenicity. Our study provides rationale for further testing LAG3 DNA methylation as a predictive biomarker for response to LAG3 immune checkpoint inhibitors.

SUBMITTER: Klumper N

PROVIDER: S-EPMC7174079 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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<i>LAG3</i> (<i>LAG-3</i>, <i>CD223</i>) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma.

Klümper Niklas N Ralser Damian J DJ Bawden Emma Grace EG Landsberg Jenny J Zarbl Romina R Kristiansen Glen G Toma Marieta M Ritter Manuel M Hölzel Michael M Ellinger Jörg J Dietrich Dimo D

Journal for immunotherapy of cancer 20200301 1

<h4>Background</h4>Lymphocyte activating 3 (LAG3, LAG-3, CD223) is a promising target for immune checkpoint inhibition in clear cell renal cell carcinoma (KIRC). The aim of this study was to investigate the epigenetic regulation of <i>LAG3</i> in KIRC by methylation.<h4>Methods</h4>We correlated quantitative <i>LAG3</i> methylation levels with transcriptional activity, immune cell infiltration, and overall survival in a cohort of n=533 patients with KIRC and n=160 normal adjacent tissue (NAT) sa ...[more]

PMID: 32234847

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Project description:BackgroundThe epidermal growth factor receptor (EGFR) is a primary target of molecular targeted therapy for lung adenocarcinoma (LUAD). The mechanisms that lead to epigenetic abnormalities of EGFR in LUAD are still unclear. The purpose of our study was to evaluate the abnormal methylation of EGFR CpG sites as potential biomarkers for LUAD.MethodsTo assess the differentially methylation CpG sites of EGFR in LUAD, we used an integrative study of Illumina HumanMethylation450K and RNA-seq data from The Cancer Genome Atlas (TCGA). We evaluated and compared EGFR multiple-omics data to explore the role of CpG sites located in EGFR promoter regions and gene body regions and the association with transcripts, protein expression levels, mutations, and somatic copy number variation. We calculated the correlation coefficients between CpG sites of EGFR and immune infiltration fraction (by MCPcounter and ESTIMATE) and immune-related pathways in LUAD. Finally, we validated the differential methylation of clinically and prognostically relevant CpG sites using quantitative methylation-specific PCR (qMSP).ResultsWe found that the methylation level of many EGFR CpGs in the promoter region was negatively correlated with the transcription level, protein expression, and SCNV, while the methylation at the gene body region was positively correlated with these features. The methylation level of EGFR CpGs in the promoter region was positively correlated with the level of immune infiltration and IFN-γ signature, while the opposite was found for methylation of the gene body region. The qMSP results showed that cg02316066 had a high methylation level, while cg02166842 had a low methylation level in LUAD. There was a high degree of co-methylation between cg02316066 and cg03046247.ConclusionOur data indicate that EGFR is an epigenetic regulator in LUAD acting through DNA methylation. Our research provides a theoretical basis for the further detection of EGFR DNA methylation as a predictive biomarker for LUAD survival and immunotherapy.

Project description:BACKGROUND:The co-receptor lymphocyte-activation gene-3 (LAG3, LAG-3, CD223) is a potential target for immune checkpoint inhibition immunotherapies. However, little is known about the biological and clinical significance of LAG3 DNA methylation in melanoma and its microenvironment. METHODS:We evaluated LAG3 promoter and gene body methylation in a cohort of N = 470 melanoma patients obtained from The Cancer Genome Atlas (TCGA cohort), an independent cohort of N = 120 patients from the University Hospital Bonn, and in subsets of peripheral blood leukocytes, melanocytes, and melanoma cell lines. We validated the association of LAG3 methylation with mRNA expression in vitro in the melanoma cell line A375 treated with the hypomethylating agent 5-azacytidine and stimulated with interferon-?. Finally, we investigated correlations between LAG3 methylation and progression-free survival in patients treated with immune checkpoint blockade (ICB cohort, N = 118). FINDINGS:Depending on the analysed locus (promoter, gene body) we found region-dependent significant LAG3 methylation differences between monocytes, B cells, CD8+ and CD4+ T cells, regulatory T cells, melanocytes, and melanoma cell lines. In tumor tissues, methylation correlated significantly with LAG3 mRNA expression, immune cell infiltrates (histopathologic lymphocyte score and RNA-Seq signatures of distinct immune infiltrates), and an interferon-? signature. Finally, LAG3 methylation was associated with overall survival in the TCGA cohort and progression-free survival in the ICB cohort. We detected basal LAG3 mRNA expression in the melanoma cell A375 and an interferon-? inducible expression after demethylation with 5-azacytidine. INTERPRETATION:Our study points towards an epigenetic regulation of LAG3 via promoter methylation and suggests a prognostic and predictive significance of LAG3 methylation in melanoma. Our results give insight in the tumor cell-intrinsic transcriptional regulation of LAG3 in melanoma. In perspective, our results might pave the way for investigating LAG3 methylation as a predictive biomarker for response to anti-LAG3 immune checkpoint blockage. FUNDING:A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Dataset Information

LAG3 (LAG-3, CD223) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma.

Publications

<i>LAG3</i> (<i>LAG-3</i>, <i>CD223</i>) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma.

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