{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T13:07:25Z","timestamp":1785244045525,"version":"3.55.0"},"reference-count":47,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T00:00:00Z","timestamp":1750982400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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+, CD8+, or FoxP3+ 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+ 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.<\/jats:p>","DOI":"10.3390\/cells14130985","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T07:55:43Z","timestamp":1751442943000},"page":"985","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Local T-Cell Dysregulation and Immune Checkpoint Expression in Human Papillomavirus-Mediated Recurrent Respiratory Papillomatosis"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6947-9836","authenticated-orcid":false,"given":"Hans N. C.","family":"Eckel","sequence":"first","affiliation":[{"name":"Faculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4125-6048","authenticated-orcid":false,"given":"Su Ir","family":"Lyu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and University Hospital of Cologne, Institute of Pathology, University of Cologne, 50937 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Faste","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shachi J.","family":"Sharma","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Nobis","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1092-689X","authenticated-orcid":false,"given":"Nora","family":"Wuerdemann","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, 50937 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7130-4015","authenticated-orcid":false,"given":"Maria","family":"Ziogas","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9963-1109","authenticated-orcid":false,"given":"Marcel","family":"Mayer","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0134-8509","authenticated-orcid":false,"given":"Malte C.","family":"Suchan","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Wennhold","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5923-5942","authenticated-orcid":false,"given":"Maria A.","family":"Garcia-Marquez","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2785-9726","authenticated-orcid":false,"given":"Martin","family":"Thelen","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Hagen","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Faculty of Medicine and University Hospital of Cologne, Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, 50937 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"E\u00dfer","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Klasen","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Siefer","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Otte","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1304-7719","authenticated-orcid":false,"given":"Hans A.","family":"Schloesser","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Faculty of Medicine and University Hospital of Cologne, Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, 50937 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8223-7954","authenticated-orcid":false,"given":"Jens P.","family":"Klussmann","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3537-6011","authenticated-orcid":false,"given":"Alexander","family":"Quaas","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and University Hospital of Cologne, Institute of Pathology, University of Cologne, 50937 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5028-0600","authenticated-orcid":false,"given":"Kevin K.","family":"Hansen","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and University Hospital of Cologne, Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1128\/CMR.05028-11","article-title":"Epithelial Cell Responses to Infection with Human Papillomavirus","volume":"25","author":"Stanley","year":"2012","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.otc.2008.09.007","article-title":"Palliative Aspects of Recurrent Respiratory Papillomatosis","volume":"42","author":"Johnson","year":"2009","journal-title":"Otolaryngol. Clin. N. Am."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1111\/coa.13016","article-title":"Age of Diagnosis, Incidence and Prevalence of Recurrent Respiratory Papillomatosis-A South African Perspective","volume":"43","author":"Seedat","year":"2018","journal-title":"Clin. Otolaryngol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1002\/lary.23327","article-title":"Epidemiological Aspects of Recurrent Respiratory Papillomatosis: A Population-Based Study","volume":"122","author":"Omland","year":"2012","journal-title":"Laryngoscope"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1111\/coa.12565","article-title":"Age of Onset of Recurrent Respiratory Papillomatosis: A Distribution Analysis","volume":"41","author":"Brunings","year":"2016","journal-title":"Clin. Otolaryngol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1177\/00034894231158459","article-title":"Smoking and Carcinoma Trends in Recurrent Respiratory Papillomatosis Patients","volume":"132","author":"Freeman","year":"2023","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1177\/0003489415608196","article-title":"Risk Factors for Dysplasia in Recurrent Respiratory Papillomatosis in an Adult and Pediatric Population","volume":"125","author":"Bishop","year":"2016","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1097\/MOO.0000000000000490","article-title":"Recurrent Respiratory Papillomatosis: Update 2018","volume":"26","author":"Derkay","year":"2018","journal-title":"Curr. Opin. Otolaryngol. Head Neck Surg."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/j.1440-1843.2008.01421.x","article-title":"Recurrent Respiratory Papillomatosis with Pulmonary Involvement: A Case Report and Review of the Literature","volume":"14","author":"Ruan","year":"2009","journal-title":"Respirology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1002\/lary.26742","article-title":"Laryngeal Distribution of Recurrent Respiratory Papillomatosis in a Previously Untreated Cohort","volume":"128","author":"Benedict","year":"2018","journal-title":"Laryngoscope"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4461","DOI":"10.1007\/s00405-022-07407-6","article-title":"The Predominant Site of Pharyngeal Lesions in Patients with Recurrent Respiratory Papillomatosis","volume":"279","author":"Matsuzaki","year":"2022","journal-title":"Eur. Arch. Otorhinolaryngol"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.1002\/lary.30036","article-title":"Prospective, Multi-Center Study of the Anatomic Distribution of Recurrent Respiratory Papillomatosis","volume":"132","author":"Benedict","year":"2022","journal-title":"Laryngoscope"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1111\/j.1600-0463.2010.02617.x","article-title":"Recurrent Respiratory Papillomatosis: A Complex Defect in Immune Responsiveness to Human Papillomavirus-6 and -11","volume":"118","author":"Bonagura","year":"2010","journal-title":"APMIS"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"372","DOI":"10.2119\/molmed.2014.00098","article-title":"Decreased Langerhans Cell Responses to IL-36\u03b3: Altered Innate Immunity in Patients with Recurrent Respiratory Papillomatosis","volume":"20","author":"Devoti","year":"2014","journal-title":"Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.ijporl.2017.02.022","article-title":"PD-L1 Expression and CD8+ Infiltration Shows Heterogeneity in Juvenile Recurrent Respiratory Papillomatosis","volume":"95","author":"Liu","year":"2017","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2819","DOI":"10.1002\/lary.31253","article-title":"Profiling of VEGF Receptors and Immune Checkpoints in Recurrent Respiratory Papillomatosis","volume":"134","author":"Lam","year":"2024","journal-title":"Laryngoscope"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"E27","DOI":"10.1002\/lary.26847","article-title":"The PD-1 and PD-L1 Pathway in Recurrent Respiratory Papillomatosis","volume":"128","author":"Ahn","year":"2018","journal-title":"Laryngoscope"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1158\/1078-0432.CCR-11-2941","article-title":"Immune Suppression in Premalignant Respiratory Papillomas: Enriched Functional CD4+Foxp3+ Regulatory T Cells and PD-1\/PD-L1\/L2 Expression","volume":"18","author":"Hatam","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e0094622","DOI":"10.1128\/jvi.00946-22","article-title":"Restricted Recruitment of NK Cells with Impaired Function Is Caused by HPV-Driven Immunosuppressive Microenvironment of Papillomas in Aggressive Juvenile-Onset Recurrent Respiratory Papillomatosis Patients","volume":"96","author":"Wang","year":"2022","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.otorri.2019.11.001","article-title":"Trends in Recurrent Respiratory Papillomatosis Treatment","volume":"72","author":"Ballestas","year":"2021","journal-title":"Acta. Otorrinolaringol. Esp."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1080\/13102818.2014.933500","article-title":"Therapeutic Approaches to the Treatment of Recurrent Respiratory Papillomatosis of the Aerodigestive Tract (a Clinical Study)","volume":"28","author":"Avramov","year":"2014","journal-title":"Biotechnol. Biotechnol. Equip."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"47S","DOI":"10.1177\/01455613221128714","article-title":"Laryngotracheal Recurrent Papillomatosis: A Case Study and Survey of Surgical and Systemic Management","volume":"101","author":"Borrelli","year":"2022","journal-title":"Ear Nose Throat. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/j.otohns.2006.09.007","article-title":"Antiviral Agents for the Treatment of Recurrent Respiratory Papillomatosis: A Systematic Review of the English-Language Literature","volume":"136","author":"Chadha","year":"2007","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1056\/NEJM199108293250904","article-title":"Long-Term Response of Recurrent Respiratory Papillomatosis to Treatment with Lymphoblastoid Interferon Alfa-N1. Papilloma Study Group","volume":"325","author":"Leventhal","year":"1991","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41541-023-00644-8","article-title":"Recurrent Respiratory Papillomatosis (RRP)-Meta-Analyses on the Use of the HPV Vaccine as Adjuvant Therapy","volume":"8","author":"Goon","year":"2023","journal-title":"NPJ Vaccines"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"596-614.e14","DOI":"10.1016\/j.cell.2021.01.002","article-title":"Meta-Analysis of Tumor- and T Cell-Intrinsic Mechanisms of Sensitization to Checkpoint Inhibition","volume":"184","author":"Litchfield","year":"2021","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2483","DOI":"10.1007\/s00262-023-03441-3","article-title":"The Landscape of Objective Response Rate of Anti-PD-1\/L1 Monotherapy across 31 Types of Cancer: A System Review and Novel Biomarker Investigating","volume":"72","author":"Mao","year":"2023","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/s40425-019-0603-3","article-title":"Safety and Clinical Activity of PD-L1 Blockade in Patients with Aggressive Recurrent Respiratory Papillomatosis","volume":"7","author":"Allen","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1634\/theoncologist.2018-0505","article-title":"Clinical Activity of Nivolumab for Human Papilloma Virus-Related Juvenile-Onset Recurrent Respiratory Papillomatosis","volume":"24","author":"Creelan","year":"2019","journal-title":"Oncologist"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Bankhead, P., Loughrey, M.B., Fern\u00e1ndez, J.A., Dombrowski, Y., McArt, D.G., Dunne, P.D., McQuaid, S., Gray, R.T., Murray, L.J., and Coleman, H.G. (2017). QuPath: Open Source Software for Digital Pathology Image Analysis. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-17204-5"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1017\/S0022215121002322","article-title":"Infantile Recurrent Respiratory Papillomatosis: Review of Adjuvant Therapies","volume":"135","author":"Patel","year":"2021","journal-title":"J. Laryngol. Otol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"11422","DOI":"10.1128\/JVI.05608-11","article-title":"Increased Frequency of Regulatory T Cells Accompanies Increased Immune Activation in Rectal Mucosae of HIV-Positive Noncontrollers","volume":"85","author":"Shaw","year":"2011","journal-title":"J. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/S0140-6736(05)67069-9","article-title":"Worldwide Distribution of Human Papillomavirus Types in Cytologically Normal Women in the International Agency for Research on Cancer HPV Prevalence Surveys: A Pooled Analysis","volume":"366","author":"Clifford","year":"2005","journal-title":"Lancet"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1038\/nri1665","article-title":"Two Sides of a Cellular Coin: CD4+CD3\u2212 Cells Regulate Memory Responses and Lymph-Node Organization","volume":"5","author":"Lane","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1002\/eji.202049028","article-title":"Human NK Cells, Their Receptors and Function","volume":"51","author":"Quatrini","year":"2021","journal-title":"Eur. J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e28303","DOI":"10.1002\/jmv.28303","article-title":"Assessment of Immunomodulation and Regulation of Cell Cycle in Epithelium and Stroma after Cidofovir Injection in Patients with Recurrent Respiratory Papillomatosis\u2014Pilot Study","volume":"95","author":"Solarz","year":"2023","journal-title":"J. Med. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"112138","DOI":"10.1016\/j.ijporl.2024.112138","article-title":"Evaluating the Efficacy and Safety of Intralesional Bevacizumab in the Treatment of Recurrent Respiratory Papillomatosis: A Systematic Review","volume":"186","author":"Walter","year":"2024","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.ijporl.2012.12.027","article-title":"Systematic Review of Intralesional Cidofovir Dosing Regimens in the Treatment of Recurrent Respiratory Papillomatosis","volume":"77","author":"Clamp","year":"2013","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5041","DOI":"10.1002\/lary.31670","article-title":"A Consensus Statement on the Administration of Systemic Bevacizumab in Patients with Recurrent Respiratory Papillomatosis","volume":"134","author":"Best","year":"2024","journal-title":"Laryngoscope"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3253","DOI":"10.1002\/lary.31387","article-title":"Systemic Bevacizumab for Recurrent Respiratory Papillomatosis: A Single Institution\u2019s Experience","volume":"134","author":"So","year":"2024","journal-title":"Laryngoscope"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"637.e1","DOI":"10.1016\/j.jvoice.2021.03.017","article-title":"Stabilization of Recurrent Respiratory Papillomatosis with Pembrolizumab Therapy: A Case Report","volume":"37","author":"Strohl","year":"2023","journal-title":"J. Voice"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1186\/s13046-019-1259-z","article-title":"Combination of CTLA-4 and PD-1 Blockers for Treatment of Cancer","volume":"38","author":"Rotte","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"22699","DOI":"10.1073\/pnas.1821218116","article-title":"Combination Anti\u2013CTLA-4 plus Anti\u2013PD-1 Checkpoint Blockade Utilizes Cellular Mechanisms Partially Distinct from Monotherapies","volume":"116","author":"Wei","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1186\/s12916-015-0455-8","article-title":"Immune Related Adverse Events Associated with Anti-CTLA-4 Antibodies: Systematic Review and Meta-Analysis","volume":"13","author":"Bertrand","year":"2015","journal-title":"BMC Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1001\/jamaoncol.2018.3923","article-title":"Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis","volume":"4","author":"Wang","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9024","DOI":"10.1200\/JCO.2023.41.16_suppl.9024","article-title":"Safety and Clinical Activity of Target-Preserving Anti-CTLA-4 Antibody ONC-392 as Monotherapy in NSCLC Patients Who Progressed on PD(L)1-Targeted Immunotherapy","volume":"41","author":"He","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2602","DOI":"10.1200\/JCO.2024.42.16_suppl.2602","article-title":"Phase 1 Study of BA3071, an Anti\u2013CTLA-4 Conditionally Active Biologic, in Combination with Nivolumab in Advanced Solid Tumors","volume":"42","author":"Thomas","year":"2024","journal-title":"J. Clin. 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