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DOI: 10.1055/s-0042-1746585
CTLA4 promoter hypomethylation predicts favorable outcome to anti-PD-1 immunotherapy in head and neck squamous cell carcinoma
Background Immune checkpoint (IC) inhibitors extended the range of therapies for recurred or metastasized head and neck squamous cell carcinoma (HNSCC). A limitation is the low response rate of only 10-15%. DNA methylation is a promising biomarker to select patients benefitting from immunotherapy. Substantiated results were observed for DNA methylation of the IC gene Tlymphocyte-associated protein 4 (CTLA4) and its predictive value.
Methods We analyzed a cohort of HNSCC patients treated at the University Medical Center Bonn (UKB ICB Cohort, N=40) under PD-1 immunotherapy. To determine CTLA4 DNA methylation, we applied a quantitative methylation-specific PCR assay to detect the methylation level of CpG sites in the central promoter region. The analysis included the correlation of CTLA4 DNA methylation with progression-free survival, overall survival, and RECIST 1.1. For further validation, we determined CTLA4 DNA methylation in a second cohort (UKB Non-ICB Cohort, N=129) that did not receive an IC inhibitor. In this cohort, we analyzed the association of CD3+, CD4+, CD8+, and CD45+ immune cells with CTLA4 DNA methylation.
Results We found lower CTLA4 DNA methylation to be significantly correlated with progression-free survival and overall-survival. In addition to that, we observed that a low CTLA4 DNA methylation was correlated with a better response to anti-PD-1 immunotherapy. A strong negative correlation of CTLA4 DNA methylation was observed with infiltrates of CD3+, CD4+, CD8+ and CD45+ immune cells.
Conclusion Our results provide first indications that CTLA4 DNA hypomethylation is associated with a favorable clinical course under immunotherapy. In the next step, we suggest to prove the predictive value of CTLA4 DNA methylation in an anti-CTLA4-treated cohort.
Publication History
Article published online:
24 May 2022
© 2022. 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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