CTLA4 promoter methylation predicts response and progression-free survival in stage IV melanoma treated with anti-CTLA-4 immunotherapy (ipilimumab)

Fietz, Simon; Zarbl, Romina; Niebel, Dennis; Posch, Christian; Brossart, Peter; Gielen, Gerrit H.; Strieth, Sebastian; Pietsch, Torsten; Kristiansen, Glen; Bootz, Friedrich; Landsberg, Jennifer; Dietrich, Dimo

doi:10.1007/s00262-020-02777-4

Cited by 22 publications

(31 citation statements)

References 26 publications

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“…Based on published researches, we observed that some studies have revealed the correlation between DNA methylation with immunotherapy and immune infiltration, which could not be elucidated from the traditional RNA regulation viewpoint. Fietz S et al examined CTLA4 promoter methylation for predicting objective response to anti-CTLA-4 immunotherapy in late-stage melanoma ( Fietz et al, 2020 ). Nair V S et al pointed out that T-cell exhaustion and immune checkpoint biomarkers were abnormally altered in tumor-infiltrating CD8 + and CD4 + T cells and tumor tissues in colorectal cancer (CRC) ( Nair et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Immunological Significance of Prognostic DNA Methylation Sites in Hepatocellular Carcinoma

Chen

et al. 2021

Front. Mol. Biosci.

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Background: Hepatocellular carcinoma (HCC) is a tumor with high morbidity and high mortality worldwide. DNA methylation, one of the most common epigenetic changes, might serve a vital regulatory role in cancer.Methods: To identify categories based on DNA methylation data, consensus clustering was employed. The risk signature was yielded by systematic bioinformatics analyses based on the remarkably methylated CpG sites of cluster 1. Kaplan–Meier analysis, variable regression analysis, and ROC curve analysis were further conducted to validate the prognosis predictive ability of risk signature. Gene set enrichment analysis (GSEA) was performed for functional annotation. To uncover the context of tumor immune microenvironment (TIME) of HCC, we employed the ssGSEA algorithm and CIBERSORT method and performed TIMER database exploration and single-cell RNA sequencing analysis. Additionally, quantitative real-time polymerase chain reaction was employed to determine the LRRC41 expression and preliminarily explore the latent role of LRRC41 in prognostic prediction. Finally, mutation data were analyzed by employing the “maftools” package to delineate the tumor mutation burden (TMB).Results: HCC samples were assigned into seven subtypes with different overall survival and methylation levels based on 5′-cytosine-phosphate-guanine-3′ (CpG) sites. The risk prognostic signature including two candidate genes (LRRC41 and KIAA1429) exhibited robust prognostic predictive accuracy, which was validated in the external testing cohort. Then, the risk score was significantly correlated with the TIME and immune checkpoint blockade (ICB)–related genes. Besides, a prognostic nomogram based on the risk score and clinical stage presented powerful prognostic ability. Additionally, LRRC41 with prognostic value was corroborated to be closely associated with TIME characterization in both expression and methylation levels. Subsequently, the correlation regulatory network uncovered the potential targets of LRRC41 and KIAA1429. Finally, the methylation level of KIAA1429 was correlated with gene mutation status.Conclusion: In summary, this is the first to identify HCC samples into distinct clusters according to DNA methylation and yield the CpG-based prognostic signature and quantitative nomogram to precisely predict prognosis. And the pivotal player of DNA methylation of genes in the TIME and TMB status was explored, contributing to clinical decision-making and personalized prognosis monitoring of HCC.

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Section: Discussionmentioning

confidence: 99%

Immunological Significance of Prognostic DNA Methylation Sites in Hepatocellular Carcinoma

Chen

et al. 2021

Front. Mol. Biosci.

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“…Distinct epigenetic signatures show promise for assisting in distinguishing between benign and malignant lesions, as well as between certain disease subtypes histologically classified or evaluated into blood circulation [ 34 , 103 , 285 ]. Moreover, altered epigenetic patterns have been shown to contribute to the acquisition of drug resistant phenotypes in CM and some of these modifications seem to have important prognostic and predictive applications [ 189 , 195 ]. Given the critical roles of epigenetic alterations in CM development and drug resistance, but also their reversible nature, targeting or co-targeting these epigenetic events appears to be a promising strategy for improving the clinical condition of CM patients.…”

Section: Discussionmentioning

confidence: 99%

“…Several authors have reported a mechanistic link between DNA methylation status and immune checkpoint gene expression that may have important predictive and monitoring implications for immunotherapy-treated CM patients. For instance, methylation of immune checkpoint CTLA4 has recently been associated with worse response and progression-free survival (PFS) in stage IV CM patients treated with ipilimumab [ 189 ]. The same study also highlighted an inverse correlation between CTLA4 promoter methylation and the presence of tumor-infiltrating lymphocytes (TILs), which play a critical role in tumor control and response to immunotherapy.…”

Section: Epigenetic Alterations Involved In CM Drug Resistancementioning

confidence: 99%

“…Therefore, melanoma samples with a low level of methylation are likely to have an increased immune cell infiltration, and an increased number of TILs is an indicator of a good clinical response. However, no significant correlation was reported between CTLA4 promoter methylation and CTLA-4 protein expression, suggesting that the level of protein expression of CTLA4 cannot be used as a predictive biomarker in CM [ 189 ]. Other authors have shown that the pattern of PD-L1 methylation may also be suggestive of the response to immunotherapy.…”

Section: Epigenetic Alterations Involved In CM Drug Resistancementioning

confidence: 99%

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Interrogating Epigenome toward Personalized Approach in Cutaneous Melanoma

Dobre

Constantin

Costache

et al. 2021

JPM

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Epigenetic alterations have emerged as essential contributors in the pathogenesis of various human diseases, including cutaneous melanoma (CM). Unlike genetic changes, epigenetic modifications are highly dynamic and reversible and thus easy to regulate. Here, we present a comprehensive review of the latest research findings on the role of genetic and epigenetic alterations in CM initiation and development. We believe that a better understanding of how aberrant DNA methylation and histone modifications, along with other molecular processes, affect the genesis and clinical behavior of CM can provide the clinical management of this disease a wide range of diagnostic and prognostic biomarkers, as well as potential therapeutic targets that can be used to prevent or abrogate drug resistance. We will also approach the modalities by which these epigenetic alterations can be used to customize the therapeutic algorithms in CM, the current status of epi-therapies, and the preliminary results of epigenetic and traditional combinatorial pharmacological approaches in this fatal disease.

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“…22,23 Recently, methylation of the CTLA-4 encoding gene has been shown to predict response to anti-CTLA-4 immunotherapy in melanoma. 24 The aim of our study is a detailed description of the DNA methylation landscape within GITR and OX40, both located in close proximity on chromosome 1 p36.33, in HNSCC. In our analysis we follow-up on our hypothesis that OX40 and GITR mRNA expression is regulated by DNA methylation.…”

mentioning

confidence: 99%

DNA Methylation and mRNA Expression of OX40 (TNFRSF4) and GITR (TNFRSF18, AITR) in Head and Neck Squamous Cell Carcinoma Correlates With HPV Status, Mutational Load, an Interferon-γ Signature, Signatures of Immune Infiltrates, and Survival

Loick

Fröhlich

Gabrielpillai

et al. 2021

Journal of Immunotherapy

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The tumor necrosis factor receptor superfamily members 4 (TNFRSF4, OX40) and 18 (TNFRSF18, GITR, AITR) are under investigation as targets for immunotherapy of various cancers, including head and neck squamous cell carcinomas. Understanding the regulation of OX40 and GITR, particularly on an epigenetic level, might help to develop companion predictive biomarkers. We conducted broad correlation analyses of DNA methylation of 46 CpG sites within the GITR/ OX40 gene locus in head and neck squamous cell carcinomas and normal adjacent tissues provided by The Cancer Genome Atlas (TCGA) Research Network. We analyzed methylation levels with regard to transcriptional gene activity (mRNA expression), human papillomavirus (HPV) infection, differential methylation between tumors and normal adjacent tissues, signatures of immune cell infiltrates, an interferon-γ signature, mutational load, and overall survival. Moreover, we investigated methylation levels in HPV-positive and HPVnegative cell lines and in isolated monocytes, granulocytes, CD8 + and CD4 + T cells, and B cells from peripheral blood from healthy donors. Our results revealed a complex and sequence-contextual methylation pattern in accordance with features of epigenetic regulated genes. We detected significant methylation differences between normal adjacent and tumor tissues, between HPV-positive and HPV-negative tumors, between tumor and immune cells, and significant correlations between methylation and mRNA expression. We further found significant correlations of CpG methylation with overall survival, signatures of immune cell infiltrates, an interferon-γ signature, and mutational load.Our study provides a framework to prospectively test specific CpG sites as biomarkers, in particular in the context of immunotherapies.

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CTLA4 promoter methylation predicts response and progression-free survival in stage IV melanoma treated with anti-CTLA-4 immunotherapy (ipilimumab)

Cited by 22 publications

References 26 publications

Immunological Significance of Prognostic DNA Methylation Sites in Hepatocellular Carcinoma

Immunological Significance of Prognostic DNA Methylation Sites in Hepatocellular Carcinoma

Interrogating Epigenome toward Personalized Approach in Cutaneous Melanoma

DNA Methylation and mRNA Expression of OX40 (TNFRSF4) and GITR (TNFRSF18, AITR) in Head and Neck Squamous Cell Carcinoma Correlates With HPV Status, Mutational Load, an Interferon-γ Signature, Signatures of Immune Infiltrates, and Survival

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