Local T-Cell Dysregulation and Immune Checkpoint Expression in Human Papillomavirus-Mediated Recurrent Respiratory Papillomatosis
Human papillomavirus-mediated recurrent respiratory papillomatosis (RRP) is a premalignant neoplasia of the upper airway characterized by significant dysphonia and respiratory obstruction. Immune checkpoint blockade has emerged as a potential alternative to repeated surgical interventions in RRP. He...
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2025-06-01
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| author | Hans N. C. Eckel Su Ir Lyu Frederik Faste Shachi J. Sharma Anne Nobis Nora Wuerdemann Maria Ziogas Marcel Mayer Malte C. Suchan Kerstin Wennhold Maria A. Garcia-Marquez Martin Thelen Elena Hagen Julia Eßer Charlotte Klasen Oliver Siefer Martin Otte Hans A. Schloesser Jens P. Klussmann Alexander Quaas Kevin K. Hansen |
| author_facet | Hans N. C. Eckel Su Ir Lyu Frederik Faste Shachi J. Sharma Anne Nobis Nora Wuerdemann Maria Ziogas Marcel Mayer Malte C. Suchan Kerstin Wennhold Maria A. Garcia-Marquez Martin Thelen Elena Hagen Julia Eßer Charlotte Klasen Oliver Siefer Martin Otte Hans A. Schloesser Jens P. Klussmann Alexander Quaas Kevin K. Hansen |
| author_sort | Hans N. C. Eckel |
| collection | DOAJ |
| description | Human papillomavirus-mediated recurrent respiratory papillomatosis (RRP) is a premalignant neoplasia of the upper airway characterized by significant dysphonia and respiratory obstruction. Immune checkpoint blockade has emerged as a potential alternative to repeated surgical interventions in RRP. Here, we investigated the intralesional T-cell composition and expression of the immune checkpoints programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) in RRP. We analyzed tissue samples from 30 patients treated at a tertiary care center between 2009 and 2021, including paired samples from individual patients collected at different time points. Immunohistochemical staining was performed for CD4, CD8, CTLA-4, FoxP3, and PD-L1 and correlated with disease severity and previous adjuvant therapies. Overall disease burden and intervention-free survival were not associated with the abundance of CD4<sup>+</sup>, CD8<sup>+</sup>, or FoxP3<sup>+</sup> T cells, nor with immune checkpoint expression. However, patients with aggressive disease exhibited a higher intralesional FoxP3/CD4 T-cell ratio. Prior intralesional cidofovir treatment was associated with reduced CD4<sup>+</sup> T-cell infiltration. These findings suggest that a locally immunosuppressive microenvironment, reflected by an elevated FoxP3/CD4 ratio, contributes to disease severity in RRP. Consistent CTLA-4 expression across all evaluated samples supports further investigation of anti-CTLA-4 therapy, either alone or in combination with other checkpoint inhibitors. |
| format | Article |
| id | doaj-art-e3a791a15d924be2a0bef2d1205ab942 |
| institution | OA Journals |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj-art-e3a791a15d924be2a0bef2d1205ab9422025-08-20T02:35:59ZengMDPI AGCells2073-44092025-06-01141398510.3390/cells14130985Local T-Cell Dysregulation and Immune Checkpoint Expression in Human Papillomavirus-Mediated Recurrent Respiratory PapillomatosisHans N. C. Eckel0Su Ir Lyu1Frederik Faste2Shachi J. Sharma3Anne Nobis4Nora Wuerdemann5Maria Ziogas6Marcel Mayer7Malte C. Suchan8Kerstin Wennhold9Maria A. Garcia-Marquez10Martin Thelen11Elena Hagen12Julia Eßer13Charlotte Klasen14Oliver Siefer15Martin Otte16Hans A. Schloesser17Jens P. Klussmann18Alexander Quaas19Kevin K. Hansen20Faculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, GermanyFaculty of Medicine and University Hospital of Cologne, Institute of Pathology, University of Cologne, 50937 Cologne, GermanyFaculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, GermanyFaculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, GermanyFaculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, GermanyCenter for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, GermanyFaculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, GermanyFaculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, GermanyFaculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, GermanyCenter for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, GermanyCenter for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, GermanyCenter for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, GermanyCenter for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, GermanyFaculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, GermanyFaculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, GermanyCenter for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, GermanyFaculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, GermanyCenter for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, GermanyFaculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, GermanyFaculty of Medicine and University Hospital of Cologne, Institute of Pathology, University of Cologne, 50937 Cologne, GermanyFaculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, GermanyHuman papillomavirus-mediated recurrent respiratory papillomatosis (RRP) is a premalignant neoplasia of the upper airway characterized by significant dysphonia and respiratory obstruction. Immune checkpoint blockade has emerged as a potential alternative to repeated surgical interventions in RRP. Here, we investigated the intralesional T-cell composition and expression of the immune checkpoints programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) in RRP. We analyzed tissue samples from 30 patients treated at a tertiary care center between 2009 and 2021, including paired samples from individual patients collected at different time points. Immunohistochemical staining was performed for CD4, CD8, CTLA-4, FoxP3, and PD-L1 and correlated with disease severity and previous adjuvant therapies. Overall disease burden and intervention-free survival were not associated with the abundance of CD4<sup>+</sup>, CD8<sup>+</sup>, or FoxP3<sup>+</sup> T cells, nor with immune checkpoint expression. However, patients with aggressive disease exhibited a higher intralesional FoxP3/CD4 T-cell ratio. Prior intralesional cidofovir treatment was associated with reduced CD4<sup>+</sup> T-cell infiltration. These findings suggest that a locally immunosuppressive microenvironment, reflected by an elevated FoxP3/CD4 ratio, contributes to disease severity in RRP. Consistent CTLA-4 expression across all evaluated samples supports further investigation of anti-CTLA-4 therapy, either alone or in combination with other checkpoint inhibitors.https://www.mdpi.com/2073-4409/14/13/985human papillomavirusrecurrent respiratory papillomatosislymphocytesCTLA4 |
| spellingShingle | Hans N. C. Eckel Su Ir Lyu Frederik Faste Shachi J. Sharma Anne Nobis Nora Wuerdemann Maria Ziogas Marcel Mayer Malte C. Suchan Kerstin Wennhold Maria A. Garcia-Marquez Martin Thelen Elena Hagen Julia Eßer Charlotte Klasen Oliver Siefer Martin Otte Hans A. Schloesser Jens P. Klussmann Alexander Quaas Kevin K. Hansen Local T-Cell Dysregulation and Immune Checkpoint Expression in Human Papillomavirus-Mediated Recurrent Respiratory Papillomatosis Cells human papillomavirus recurrent respiratory papillomatosis lymphocytes CTLA4 |
| title | Local T-Cell Dysregulation and Immune Checkpoint Expression in Human Papillomavirus-Mediated Recurrent Respiratory Papillomatosis |
| title_full | Local T-Cell Dysregulation and Immune Checkpoint Expression in Human Papillomavirus-Mediated Recurrent Respiratory Papillomatosis |
| title_fullStr | Local T-Cell Dysregulation and Immune Checkpoint Expression in Human Papillomavirus-Mediated Recurrent Respiratory Papillomatosis |
| title_full_unstemmed | Local T-Cell Dysregulation and Immune Checkpoint Expression in Human Papillomavirus-Mediated Recurrent Respiratory Papillomatosis |
| title_short | Local T-Cell Dysregulation and Immune Checkpoint Expression in Human Papillomavirus-Mediated Recurrent Respiratory Papillomatosis |
| title_sort | local t cell dysregulation and immune checkpoint expression in human papillomavirus mediated recurrent respiratory papillomatosis |
| topic | human papillomavirus recurrent respiratory papillomatosis lymphocytes CTLA4 |
| url | https://www.mdpi.com/2073-4409/14/13/985 |
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