DNA methylation profiles differ in responders versus non-responders to anti-PD-1 immune checkpoint inhibitors in patients with advanced and metastatic head and neck squamous cell carcinoma
Background Biomarkers for response prediction to anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICI) in patients with head and neck squamous cell carcinoma (HNSCC) are urgently needed for a personalized therapy approach. We investigated the predictive potential of inflammatory par...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e003420.full |
| _version_ | 1797771733200011264 |
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| author | Matthias Preusser Anna Sophie Berghoff Thorsten Fuereder Leonhard Müllauer Gerwin Heller Angelika Martina Starzer Katharina Feldmann Erwin Tomasich Teresa Hatziioannou Stefan Traint Thomas Melchardt Christoph Minichsdorfer Ursula Schwarz-Nemec Maja Nackenhorst |
| author_facet | Matthias Preusser Anna Sophie Berghoff Thorsten Fuereder Leonhard Müllauer Gerwin Heller Angelika Martina Starzer Katharina Feldmann Erwin Tomasich Teresa Hatziioannou Stefan Traint Thomas Melchardt Christoph Minichsdorfer Ursula Schwarz-Nemec Maja Nackenhorst |
| author_sort | Matthias Preusser |
| collection | DOAJ |
| description | Background Biomarkers for response prediction to anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICI) in patients with head and neck squamous cell carcinoma (HNSCC) are urgently needed for a personalized therapy approach. We investigated the predictive potential of inflammatory parameters and DNA methylation profiling in patients with HNSCC treated with anti-PD-1 ICI.Methods We identified patients with HNSCC that were treated with anti-PD-1 ICI therapy in the recurrent or metastatic setting after progression to platinum-based chemotherapy in two independent centers. We analyzed DNA methylation profiles of >850.000 CpG sites in tumor specimens of these patients by Infinium MethylationEPIC microarrays, immune cell density in the tumor microenvironment (CD8, CD3, CD45RO, forkhead box P3 (FOXP3), CD68), PD-1 and programmed cell death ligand 1 (PD-L1) expression by immunohistochemistry, and blood inflammation markers (platelet-to-lymphocyte ratio, leucocyte-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio). DNA methylation profiles and immunological markers were bioinformatically and statistically correlated with radiological response to anti-PD-1 ICI.Results 37 patients with HNSCC (median age of 62 years; range 49–83; 8 (21.6%) women, 29 (78.4%) men) were included (Center 1 N=26, 70.3%; Center 2 N=11, 29.7%). Median number of prior systemic therapies was 1 (range 1–4). Five out of 37 (13.5%) patients achieved an objective response to ICI. Median progression-free survival and median overall survival times were 3.7 months (range 0–22.9) and 9.0 months (range 0–38.8), respectively. Microarray analyses revealed a methylation signature including both hypomethylation and hypermethylation which was predictive for response to ICI and included several genes involved in cancer-related molecular pathways. Over-represented differentially methylated genes between responders and non-responders were associated with ‘Axon guidance’, ‘Hippo signaling’, ‘Pathways in cancer’ and ‘MAPK signaling’. A statistically significant correlation of PD-L1 expression and response was present (p=0.0498).Conclusions Our findings suggest that tumor DNA methylation profiling may be useful to predict response to ICI in patients with HNSCC. |
| first_indexed | 2024-03-12T21:41:52Z |
| format | Article |
| id | doaj.art-e6550fd49f974f6795b61c4497460f1c |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-12T21:41:52Z |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-e6550fd49f974f6795b61c4497460f1c2023-07-26T22:10:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-003420DNA methylation profiles differ in responders versus non-responders to anti-PD-1 immune checkpoint inhibitors in patients with advanced and metastatic head and neck squamous cell carcinomaMatthias Preusser0Anna Sophie Berghoff1Thorsten Fuereder2Leonhard Müllauer3Gerwin Heller4Angelika Martina Starzer5Katharina Feldmann6Erwin Tomasich7Teresa Hatziioannou8Stefan Traint9Thomas Melchardt10Christoph Minichsdorfer11Ursula Schwarz-Nemec12Maja Nackenhorst13Christian Doppler Laboratory for Personalized Immunotherapy, Department of Medicine I, Medical University of Vienna, Vienna, AustriaDepartment of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria1 Department of Medicine I, Division of Oncology, Medical University of Vienna, Wien, AustriaDepartment of Pathology, Medical University of Vienna, Vienna, AustriaDepartment of Medicine I, Christian Doppler Laboratory for Personalized Immunotherapy, Medical University of Vienna, Vienna, AustriaDivision of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, AustriaDivision of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, AustriaDepartment of Medicine I, Christian Doppler Laboratory for Personalized Immunotherapy, Medical University of Vienna, Vienna, AustriaDivision of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, AustriaDivision of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria23rd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University Salzburg, Graz, AustriaDepartment of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, AustriaDepartment of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, AustriaDepartment of Pathology, Medical University of Vienna, Vienna, AustriaBackground Biomarkers for response prediction to anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICI) in patients with head and neck squamous cell carcinoma (HNSCC) are urgently needed for a personalized therapy approach. We investigated the predictive potential of inflammatory parameters and DNA methylation profiling in patients with HNSCC treated with anti-PD-1 ICI.Methods We identified patients with HNSCC that were treated with anti-PD-1 ICI therapy in the recurrent or metastatic setting after progression to platinum-based chemotherapy in two independent centers. We analyzed DNA methylation profiles of >850.000 CpG sites in tumor specimens of these patients by Infinium MethylationEPIC microarrays, immune cell density in the tumor microenvironment (CD8, CD3, CD45RO, forkhead box P3 (FOXP3), CD68), PD-1 and programmed cell death ligand 1 (PD-L1) expression by immunohistochemistry, and blood inflammation markers (platelet-to-lymphocyte ratio, leucocyte-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio). DNA methylation profiles and immunological markers were bioinformatically and statistically correlated with radiological response to anti-PD-1 ICI.Results 37 patients with HNSCC (median age of 62 years; range 49–83; 8 (21.6%) women, 29 (78.4%) men) were included (Center 1 N=26, 70.3%; Center 2 N=11, 29.7%). Median number of prior systemic therapies was 1 (range 1–4). Five out of 37 (13.5%) patients achieved an objective response to ICI. Median progression-free survival and median overall survival times were 3.7 months (range 0–22.9) and 9.0 months (range 0–38.8), respectively. Microarray analyses revealed a methylation signature including both hypomethylation and hypermethylation which was predictive for response to ICI and included several genes involved in cancer-related molecular pathways. Over-represented differentially methylated genes between responders and non-responders were associated with ‘Axon guidance’, ‘Hippo signaling’, ‘Pathways in cancer’ and ‘MAPK signaling’. A statistically significant correlation of PD-L1 expression and response was present (p=0.0498).Conclusions Our findings suggest that tumor DNA methylation profiling may be useful to predict response to ICI in patients with HNSCC.https://jitc.bmj.com/content/10/3/e003420.full |
| spellingShingle | Matthias Preusser Anna Sophie Berghoff Thorsten Fuereder Leonhard Müllauer Gerwin Heller Angelika Martina Starzer Katharina Feldmann Erwin Tomasich Teresa Hatziioannou Stefan Traint Thomas Melchardt Christoph Minichsdorfer Ursula Schwarz-Nemec Maja Nackenhorst DNA methylation profiles differ in responders versus non-responders to anti-PD-1 immune checkpoint inhibitors in patients with advanced and metastatic head and neck squamous cell carcinoma Journal for ImmunoTherapy of Cancer |
| title | DNA methylation profiles differ in responders versus non-responders to anti-PD-1 immune checkpoint inhibitors in patients with advanced and metastatic head and neck squamous cell carcinoma |
| title_full | DNA methylation profiles differ in responders versus non-responders to anti-PD-1 immune checkpoint inhibitors in patients with advanced and metastatic head and neck squamous cell carcinoma |
| title_fullStr | DNA methylation profiles differ in responders versus non-responders to anti-PD-1 immune checkpoint inhibitors in patients with advanced and metastatic head and neck squamous cell carcinoma |
| title_full_unstemmed | DNA methylation profiles differ in responders versus non-responders to anti-PD-1 immune checkpoint inhibitors in patients with advanced and metastatic head and neck squamous cell carcinoma |
| title_short | DNA methylation profiles differ in responders versus non-responders to anti-PD-1 immune checkpoint inhibitors in patients with advanced and metastatic head and neck squamous cell carcinoma |
| title_sort | dna methylation profiles differ in responders versus non responders to anti pd 1 immune checkpoint inhibitors in patients with advanced and metastatic head and neck squamous cell carcinoma |
| url | https://jitc.bmj.com/content/10/3/e003420.full |
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