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Published on: April 22, 2019
CTLA4 DNA methylation is associated with CTLA-4 expression and predicts response to immunotherapy in head and neck
Friederike Hoffmann1, Alina Franzen2, Luka de Vos1,2
1Department of Dermatology and Allergy, University Medical Center Bonn, Bonn, Germany.
Background:
The majority of patients with recurrent or metastasized head and neck squamous cell carcinoma (HNSCC) do not benefit from immune checkpoint blockade (ICB) while several patients experience severe and persistent immune-mediated side effects. Therefore, predictive biomarkers are urgently needed to allow for a personalized treatment. In this study, we investigated DNA methylation of the immune checkpoint gene CTLA4 with regard to its predictive value.
Methods:
We analyzed CTLA4 promoter methylation in tumors of HNSCC patients (N = 29) treated with ICB at the University Medical Center Bonn with regard to response to ICB and progression-free survival. We further analyzed a second cohort (N = 138) of patients that did not receive ICB with regard to CTLA4 promoter methylation, CTLA-4 protein expression, and immune cell infiltrates. Finally, we tested inducibility of CTLA-4 protein expression in HNSCC cells using the DNA methyltransferase inhibitor decitabine.
Results:
Lower CTLA4 promoter methylation correlated with response to ICB and prolonged progression-free survival. We could show that not only tumor infiltrating immune cells, but also HNSCC cells harbor cytoplasmic and nuclear CTLA-4 expression. CTLA4 promoter methylation inversely correlated with infiltrates of CD3+, CD4+, CD8+, and CD45+ immune cells. CTLA4 methylation did not correlate with protein expression in tumors, however, decitabine treatment led to decreased CTLA4 methylation and an induction of CTLA4 mRNA and CTLA-4 protein expression in HNSCC cell lines.
Conclusions:
Our results indicate that CTLA4 DNA hypomethylation is a predictive biomarker for response to ICB in HNSCC. Our study warrants further analyses of the predictive value of CTLA4 DNA methylation in clinical trials of anti-PD-1 and/or anti-CTLA-4 immunotherapy in HNSCC.
Insights
Lower CTLA4 promoter methylation predicts better response to immune checkpoint blockade (ICB) in head and neck squamous cell carcinoma (HNSCC). This finding may guide personalized immunotherapy for HNSCC patients.
Area of Science:
- Oncology
- Immunology
- Epigenetics
Background:
- Immune checkpoint blockade (ICB) offers limited benefit for many head and neck squamous cell carcinoma (HNSCC) patients.
- Predictive biomarkers are crucial for personalizing ICB treatment and mitigating severe side effects.
- This study investigates the predictive potential of CTLA4 gene DNA methylation in HNSCC.
Purpose of the Study:
- To evaluate CTLA4 promoter DNA methylation as a predictive biomarker for ICB response in HNSCC.
- To correlate CTLA4 methylation with clinical outcomes, including response and progression-free survival.
- To explore the relationship between CTLA4 methylation, protein expression, and immune cell infiltration in HNSCC.
Main Methods:
- Analyzed CTLA4 promoter methylation in HNSCC tumors from patients treated with ICB (N=29) and a control cohort (N=138).
- Assessed CTLA-4 protein expression and immune cell infiltrates in the control cohort.
- Investigated CTLA-4 expression induction in HNSCC cell lines treated with decitabine, a DNA methyltransferase inhibitor.
Main Results:
- Reduced CTLA4 promoter methylation was associated with positive ICB response and longer progression-free survival.
- CTLA-4 protein was expressed in both tumor-infiltrating immune cells and HNSCC cells.
- CTLA4 promoter methylation inversely correlated with CD3+, CD4+, CD8+, and CD45+ immune cell infiltrates.
- Decitabine treatment decreased CTLA4 methylation and increased CTLA4 mRNA and protein expression in HNSCC cell lines.
Conclusions:
- CTLA4 DNA hypomethylation serves as a predictive biomarker for ICB response in HNSCC.
- Further clinical trials are warranted to validate CTLA4 DNA methylation's predictive value in anti-PD-1 and anti-CTLA-4 therapies for HNSCC.
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