{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:54:32Z","timestamp":1790949272665,"version":"4.1.0"},"reference-count":32,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T00:00:00Z","timestamp":1707436800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The prognostic significance of tumor-infiltrating neutrophils in head and neck squamous cell carcinoma (HNSCC) is poorly understood. It is unclear how the presence of neutrophils affects prognosis due to their polarization into cytotoxic N1 or immunosuppressive N2. Therefore, we determined the number of CD66b+ neutrophil granulocytes separately in the stromal and epithelial compartments in cancer tissues from 397 patients with HNSCC. Tumor samples from six historical patient groups were processed into tissue microarrays and stained immunohistochemically. In total, 21.9% were HPV positive (p16+). Neutrophil counts were much lower in the stromal compartment (372 \u00b1 812) than in the epithelial cancer compartment (1040 \u00b1 1477) (p &lt; 0.001), with large differences between groups. In three groups with high neutrophil infiltration, high rates were associated with a favorable prognosis, whereas in two groups, high rates were a negative prognostic factor. In p16- oropharyngeal and hypopharyngeal cancer high infiltration was associated with a favorable prognosis. Cancers with an exclusion of neutrophils in the epithelial compartment were associated with improved prognosis. In oropharyngeal and hypopharyngeal HPV-negative cancer high neutrophil infiltration rates were clearly associated with prolonged survival. Neutrophil granulocytes in HNSCC may contribute to a favorable or unfavorable prognosis.<\/jats:p>","DOI":"10.3390\/biom14020205","type":"journal-article","created":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T03:53:46Z","timestamp":1707450826000},"page":"205","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Neutrophils in HNSCC Can Be Associated with Both a Worse or Favorable Prognosis"],"prefix":"10.3390","volume":"14","author":[{"given":"Hendrik","family":"Brunkhorst","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"},{"name":"Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0418-4401","authenticated-orcid":false,"given":"S\u00f6ren","family":"Schnellhardt","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"},{"name":"Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany"},{"name":"Department of Radiotherapy and Radiation Oncology, Saarland University Medical Center, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9974-6683","authenticated-orcid":false,"given":"Maike","family":"B\u00fcttner-Herold","sequence":"additional","affiliation":[{"name":"Department of Nephropathology, Institute of Pathology, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6803-4755","authenticated-orcid":false,"given":"Christoph","family":"Daniel","sequence":"additional","affiliation":[{"name":"Department of Nephropathology, Institute of Pathology, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4387-3285","authenticated-orcid":false,"given":"Rainer","family":"Fietkau","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"},{"name":"Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8040-3226","authenticated-orcid":false,"given":"Luitpold V.","family":"Distel","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"},{"name":"Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1159\/000438523","article-title":"Prognostic Role of Tumor-Infiltrating Lymphocytes in Lung Cancer: A Meta-Analysis","volume":"37","author":"Geng","year":"2015","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41572-020-00224-3","article-title":"Head and neck squamous cell carcinoma","volume":"6","author":"Johnson","year":"2020","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e89829","DOI":"10.1172\/jci.insight.89829","article-title":"The head and neck cancer immune landscape and its immunotherapeutic implications","volume":"1","author":"Mandal","year":"2016","journal-title":"JCI Insight"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/s00066-021-01856-4","article-title":"Head and neck tumor cells treated with hypofractionated irradiation die via apoptosis and are better taken up by M1-like macrophages","volume":"198","author":"Wedekind","year":"2022","journal-title":"Strahlenther. Onkol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1007\/s00066-023-02119-0","article-title":"Utility of pre-chemoradiotherapy Pan-Immune-Inflammation-Value for predicting the osteoradionecrosis rates in locally advanced nasopharyngeal cancers","volume":"199","author":"Yilmaz","year":"2023","journal-title":"Strahlenther. Onkol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1002\/mc.23162","article-title":"Tumor immune microenvironment in head and neck cancers","volume":"59","author":"Chen","year":"2020","journal-title":"Mol. Carcinog."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.omto.2021.01.011","article-title":"Tumor microenvironment and immune-related therapies of head and neck squamous cell carcinoma","volume":"20","author":"Qin","year":"2021","journal-title":"Mol. Ther. Oncolytics"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s12943-019-0983-5","article-title":"Effect of tumor microenvironment on pathogenesis of the head and neck squamous cell carcinoma: A systematic review","volume":"18","author":"Peltanova","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Echarti, A., Hecht, M., Buttner-Herold, M., Haderlein, M., Hartmann, A., Fietkau, R., and Distel, L. (2019). CD8+ and Regulatory T cells Differentiate Tumor Immune Phenotypes and Predict Survival in Locally Advanced Head and Neck Cancer. Cancers, 11.","DOI":"10.3390\/cancers11091398"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3293","DOI":"10.1200\/JCO.2015.61.1509","article-title":"Immunology and Immunotherapy of Head and Neck Cancer","volume":"33","author":"Ferris","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-030-35723-8_1","article-title":"Neutrophils in the Tumor Microenvironment","volume":"1224","author":"Wu","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/s11912-020-00938-3","article-title":"The Immune Microenvironment in Head and Neck Squamous Cell Carcinoma: On Subsets and Subsites","volume":"22","author":"Wondergem","year":"2020","journal-title":"Curr. Oncol. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.3389\/fonc.2019.01146","article-title":"Tumor Associated Neutrophils. Their Role in Tumorigenesis, Metastasis, Prognosis and Therapy","volume":"9","author":"Masucci","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1002\/ijc.29945","article-title":"Type I IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human","volume":"138","author":"Andzinski","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ccr.2009.06.017","article-title":"Polarization of tumor-associated neutrophil phenotype by TGF-beta: \u201cN1\u201d versus \u201cN2\u201d TAN","volume":"16","author":"Fridlender","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"342","DOI":"10.4049\/jimmunol.161.1.342","article-title":"Reduced tumorigenicity and augmented leukocyte infiltration after monocyte chemotactic protein-3 (MCP-3) gene transfer: Perivascular accumulation of dendritic cells in peritumoral tissue and neutrophil recruitment within the tumor","volume":"161","author":"Fioretti","year":"1998","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1093\/carcin\/bgs123","article-title":"Tumor-associated neutrophils: Friend or foe?","volume":"33","author":"Fridlender","year":"2012","journal-title":"Carcinogenesis"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.it.2015.11.008","article-title":"Neutrophils in the Tumor Microenvironment","volume":"37","author":"Powell","year":"2016","journal-title":"Trends Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e1232221","DOI":"10.1080\/2162402X.2016.1232221","article-title":"Tumor-associated neutrophils display a distinct N1 profile following TGFbeta modulation: A transcriptomics analysis of pro- vs. antitumor TANs","volume":"5","author":"Shaul","year":"2016","journal-title":"Oncoimmunology"},{"key":"ref_20","first-page":"141","article-title":"Polymorphonuclear Neutrophils and Tumors: Friend or Foe?","volume":"113","author":"Klink","year":"2022","journal-title":"Exp. Suppl."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2456","DOI":"10.3389\/fimmu.2018.02456","article-title":"Understanding the Multifaceted Role of Neutrophils in Cancer and Autoimmune Diseases","volume":"9","author":"Wang","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1172\/JCI37223","article-title":"Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model","volume":"120","author":"Jablonska","year":"2010","journal-title":"J. Clin. Invest."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"33","DOI":"10.3389\/fimmu.2013.00033","article-title":"Neutrophils Activate Tumoral CORTACTIN to Enhance Progression of Orohypopharynx Carcinoma","volume":"4","author":"Dumitru","year":"2013","journal-title":"Front. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1002\/ijc.25892","article-title":"Polymorphonuclear granulocytes in human head and neck cancer: Enhanced inflammatory activity, modulation by cancer cells and expansion in advanced disease","volume":"129","author":"Trellakis","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.yexcr.2016.03.007","article-title":"Identification of neutrophil surface marker changes in health and inflammation using high-throughput screening flow cytometry","volume":"342","author":"Lakschevitz","year":"2016","journal-title":"Exp. Cell Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1189\/jlb.4RU0614-294R","article-title":"Neutrophils and oral squamous cell carcinoma: Lessons learned and future directions","volume":"96","author":"Magalhaes","year":"2014","journal-title":"J. Leukoc. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Sounbuli, K., Mironova, N., and Alekseeva, L. (2022). Diverse Neutrophil Functions in Cancer and Promising Neutrophil-Based Cancer Therapies. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232415827"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Hartan, R., Schnellhardt, S., Buttner-Herold, M., Daniel, C., Hartmann, A., Fietkau, R., and Distel, L. (2022). The Prognostic and Predictive Significance of Tumor-Infiltrating Memory T Cells Is Reversed in High-Risk HNSCC. Cells, 11.","DOI":"10.3390\/cells11121960"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/j.oraloncology.2012.01.024","article-title":"Radiochemotherapy induces a favourable tumour infiltrating inflammatory cell profile in head and neck cancer","volume":"48","author":"Tabachnyk","year":"2012","journal-title":"Oral. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1746149","DOI":"10.1080\/2162402X.2020.1746149","article-title":"Regulatory T cells and cytotoxic T cells close to the epithelial-stromal interface are associated with a favorable prognosis","volume":"9","author":"Rudolf","year":"2020","journal-title":"Oncoimmunology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.advms.2021.12.004","article-title":"NETs biomarkers in saliva and serum OSCC patients: One hypothesis, two conclusions","volume":"67","author":"Garley","year":"2022","journal-title":"Adv. Med. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.semcancer.2021.07.011","article-title":"Neutrophil extracellular traps in cancer","volume":"79","author":"Cristinziano","year":"2022","journal-title":"Semin. Cancer Biol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/2\/205\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:57:45Z","timestamp":1760104665000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/2\/205"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,9]]},"references-count":32,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["biom14020205"],"URL":"https:\/\/doi.org\/10.3390\/biom14020205","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,9]]}}}