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Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Adding pembrolizumab, an anti-PD-1 antibody approved for treatment of head and neck squamous cell carcinoma (HNSCC) to neoadjuvant (induction-) chemotherapy utilizing docetaxel and cisplatin (TP) followed by radiotherapy may improve outcome in larynx organ-preservation (LOP) that is investigated in the European Larynx-Organ preservation Study (ELOS). As biomarkers for response to TP and pembrolizumab +TP are missing but may include cytokines, this work aims on determining cytokines potentially linked to outcome as prognostic markers sufficient to predict and\/or monitor response to successful LOP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Collagenase IV digests were generated from 47 histopathological confirmed HNSCC tumor samples and seeded in 96-well plates containing pembrolizumab, docetaxel, cisplatin either solely or in binary or ternary combination. According to the FLAVINO protocol, supernatants were collected after 3 days, adherent cells fixed using ethanol, air-dried and pan-cytokeratin positive epithelial cells counted using fluorescence microscopy. The cytokines IL-6, IL-8, IFN-\u03b3, IP-10, MCP-1, TNF-\u03b1, and VEGF in the supernatant were quantified by sandwich ELISA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The mode of interaction between pembrolizumab and TP was assessed and correlated to outcome (overall, disease-specific and progression-free survival of patients). Suppression of MCP-1, IFN-\u03b3 and IL-6 production by pembrolizumab + TP exceeding the suppressive effect of TP was detected in the majority of samples and linked to improved survival. Multivariate Cox proportional hazard regression modeling revealed MCP-1, IFN-\u03b3 and IL-6 as independent outcome predictors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Comparing response to TP vs. pembrolizumab vs. TP + pembrolizumab may allow for identification of patients with superior outcome independent from treatment applied.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1473897","type":"journal-article","created":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T05:10:44Z","timestamp":1736917844000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Suppression of MCP-1, IFN-\u03b3 and IL-6 production of HNSCC ex vivo by pembrolizumab added to docetaxel and cisplatin (TP) exceeding those of TP alone is linked to improved survival"],"prefix":"10.3389","volume":"15","author":[{"given":"Jana","family":"Wellhausen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louisa","family":"R\u00f6hl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Berszin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Kr\u00fccken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veit","family":"Zebralla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Pirlich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthaeus","family":"Stoehr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Wiegand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Dietz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa","family":"Wald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunnar","family":"Wichmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s00117-020-00760-9","article-title":"S3-Leitlinie Diagnostik, Therapie und Nachsorge des Larynxkarzinoms","volume":"60","author":"Bootz","year":"2020","journal-title":"Radiologe"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy332","article-title":"Induction chemotherapy (IC) followed by radiotherapy (RT) versus cetuximab plus IC and RT in advanced laryngeal\/hypopharyngeal cancer resectable only by total laryngectomy-final results of the larynx organ preservation trial DeLOS-II","volume":"29","author":"Dietz","year":"2018","journal-title":"Ann Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2016.11.013","article-title":"Induction chemotherapy followed by radiotherapy for larynx preservation in advanced laryngeal and hypopharyngeal cancer: Outcome prediction after one cycle induction chemotherapy by a score based on clinical evaluation, computed tomography-based volumetry and 18F-FDG-PET\/CT","volume":"72","author":"Wichmann","year":"2017","journal-title":"Eur J Cancer"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00191","article-title":"Perspectives of Induction With Chemo and\/or Immune Check Point Inhibition in Head and Neck Organ Preservation Treatment","volume":"9","author":"Wiegand","year":"2019","journal-title":"Front Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00625","article-title":"Laryngeal preservation approaches: considerations for new selection criteria based on the deLOS-II trial","volume":"9","author":"Dietz","year":"2019","journal-title":"Front Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1394691","article-title":"Improved survival of locoregional-advanced larynx and hypopharynx cancer patients treated according to the DeLOS-II protocol","volume":"14","author":"Wichmann","year":"2024","journal-title":"Front Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1433238","article-title":"The European Larynx Organ Preservation Study (ELOS) [MK-3475-C44]: STUDY PROTOCOL article Front","volume":"14","author":"Wichmann","year":"2024","journal-title":"Oncol Sec. 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