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DOI: 10.1055/s-0041-1727985
Comprehensive analysis of LAG3 DNA methylation in head and neck squamous cell carcinomas with regard to gene expression and features predictive for response to immunotherapy
IntroductionThe immune checkpoint receptor lymphocyte-activation gene 3 (LAG3) is under investigation as novel target for immunotherapy in several solid tumors, including head and neck squamous cell carcinomas (HNSCC). Usually, only a minor portion of HNSCC patients will benefit from an immunotherapy, necessitating the development of companion predictive biomarkers. The understanding of the regulation LAG3, in particular on an epigenetic level, is mandatory for biomarker development.
Material und methodsWe analyzed LAG3 DNA methylation at single CpG site resolution in N=528 HNSCC and N=50 normal tissue samples provided by The Cancer Genome Atlas with regard to transcriptional activity, human papilloma virus (HPV) status, mutational load, immune cell infiltrates and an interferon-γ signature. We analyzed the correlation between DNA methylation and LAG3 protein expression by quantitative methylation-specific PCR and immunohistochemistry in a cohort of N=100[DDD1] . Finally, we investigated the correlation between progression-free survival and LAG3 methylation in a cohort of N=32 recurrent/metastatic HNSCC patients who received anti-PD-1 immune checkpoint blockade.
ResultsWe found strong correlations and associations between DNA methylation with gene expression and features predictive for response to immunotherapy (tumor mutational burden, interferon-γ signature, immune infiltrates, HPV-status). Data from our cohort of patients who received anti-PD-1 immunotherapy indicates the capability to predict response to immune checkpoint blockade therapy.
Discussion: Our data suggests an epigenetic regulation of LAG3 via DNA methylation in HNSCC and provides rationale for testing LAG3 methylation in a cohort of patients treated with anti-LAG3 immune checkpoint inhibitors.
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Conflict of interest
Der Erstautor gibt keinen Interessenskonflikt an.
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Publication History
Article published online:
13 May 2021
© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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