{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T04:23:42Z","timestamp":1750220622839,"version":"3.33.0"},"reference-count":29,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T00:00:00Z","timestamp":1736985600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000646","name":"Japan Society for the Promotion of Science London","doi-asserted-by":"publisher","award":["JP 21H03085, JP 20K21648"],"award-info":[{"award-number":["JP 21H03085, JP 20K21648"]}],"id":[{"id":"10.13039\/501100000646","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Cancer immune responses are generated in secondary lymphoid organs, such as the lymph nodes and tonsils. In the current study, transcriptional profiles of peritumoral tonsillar tissues (PTTs) from oropharyngeal cancers (OPCs) were assessed and compared with those of inflammatory tonsils and regional lymph nodes (rLNs).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>RNA samples of PTTs and rLNs from 13 OPCs, and 4 inflammatory tonsils were subjected to microarray analysis, and differentially expressed genes (DEGs) identified from 730 nCounter Panel immune-related genes. Gene Set enrichment Analysis (GSEA) was used for DEG profiling of PTTs and rLNs between lymph node metastasis-negative and metastasis-positive cases. The top 20 genes, as ranked by GSEA metric scores, were extracted and subjected to principal component analysis (PCA). The correlation of each patient\u2019s PCA score with lymph node status was assessed by Receiver Operating Characteristics (ROC) analysis.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Comparing DEG analyses of PTTs with those of inflammatory tonsils and rLNs revealed 144 and 45 upregulated genes, respectively. ClueGO, a widely used Cytoscape plug-in, revealed activated pathways in PTTs, including lymphocyte proliferation (followed by T cell activation involved in the immune response) and positive regulation of leukocyte migration (followed by antimicrobial humoral immune response mediated by antimicrobial peptides) as the most significantly enriched immune system process functions in the gene ontology when comparing inflammatory tonsils and rLNs. The area under the ROC curves of PTTs and rLNs were 0.806 and 0.389, and were significant by DeLong\u2019s test (p = 0.025).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>PTTs exhibit unique immunological features distinguishing them from inflammatory tonsils and rLNs. Gene expression analysis of PTTs is useful for investigating the mechanism of OPC lymphatic spread, even compared with analysis of rLNs.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0316102","type":"journal-article","created":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T18:46:11Z","timestamp":1737053171000},"page":"e0316102","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Distinct immunological features of oropharyngeal cancer peritumoral tonsillar tissues from inflammatory tonsils and regional lymph nodes: A pilot 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Network in Head and Neck Squamous Cell Carcinoma-A Prognostic Tool Beyond HPV Status.","volume":"10","author":"A Fialov\u00e1","year":"2020","journal-title":"Front Oncol"},{"issue":"7378","key":"pone.0316102.ref002","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1038\/nature10673","article-title":"Cancer immunotherapy comes of age","volume":"480","author":"I Mellman","year":"2011","journal-title":"Nature"},{"issue":"6","key":"pone.0316102.ref003","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/s41568-019-0144-6","article-title":"Tertiary lymphoid structures in the era of cancer immunotherapy","volume":"19","author":"C Saut\u00e8s-Fridman","year":"2019","journal-title":"Nat Rev Cancer"},{"issue":"5","key":"pone.0316102.ref004","doi-asserted-by":"crossref","first-page":"110331","DOI":"10.1016\/j.celrep.2022.110331","article-title":"PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes","volume":"38","author":"J Nagasaki","year":"2022","journal-title":"Cell Rep"},{"issue":"6","key":"pone.0316102.ref005","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1016\/j.cell.2023.02.021","article-title":"Dynamic CD8(+) T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes.","volume":"186","author":"MK Rahim","year":"2023","journal-title":"Cell"},{"issue":"1","key":"pone.0316102.ref006","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1159\/000024354","article-title":"The immune response in adenoids and tonsils","volume":"122","author":"MJ van Kempen","year":"2000","journal-title":"Int Arch Allergy Immunol"},{"issue":"8","key":"pone.0316102.ref007","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1016\/j.ajpath.2023.04.010","article-title":"Immune-Related Gene Expression Profile at Peritumoral Tonsillar Tissue Is Modified by Oropharyngeal Cancer Nodal Status","volume":"193","author":"N Wakisaka","year":"2023","journal-title":"Am J Pathol"},{"issue":"2","key":"pone.0316102.ref008","doi-asserted-by":"crossref","first-page":"e0299750","DOI":"10.1371\/journal.pone.0299750","article-title":"Lymph node metastasis regulation by peritumoral tonsillar tissue mitochondria-related pathway activation in oropharyngeal cancer","volume":"19","author":"N Wakisaka","year":"2024","journal-title":"PLoS One"},{"key":"pone.0316102.ref009","first-page":"17","article-title":"TNM classification of malignant tumours, eighth edn.","author":"MK James DB","year":"2017"},{"issue":"7","key":"pone.0316102.ref010","doi-asserted-by":"crossref","first-page":"3501","DOI":"10.1245\/s10434-020-09277-w","article-title":"Characterization of Sentinel Lymph Node Immune Signatures and Implications for Risk Stratification for Adjuvant Therapy in Melanoma","volume":"28","author":"NE Farrow","year":"2021","journal-title":"Ann Surg 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Microbiol"},{"issue":"1","key":"pone.0316102.ref020","doi-asserted-by":"crossref","first-page":"4036","DOI":"10.1038\/s41598-017-03466-6","article-title":"Microbial Signatures Associated with Oropharyngeal and Oral Squamous Cell Carcinomas.","volume":"7","author":"S Banerjee","year":"2017","journal-title":"Sci Rep"},{"issue":"1","key":"pone.0316102.ref021","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1080\/00016489.2018.1535193","article-title":"Detection of sentinel lymph node using contrast-enhanced agent, Sonazoid(), and evaluation of its metastasis with superb microvascular imaging in oral and oropharyngeal cancers: a preliminary clinical study.","volume":"139","author":"N Wakisaka","year":"2019","journal-title":"Acta Otolaryngol.Jan"},{"issue":"6","key":"pone.0316102.ref022","doi-asserted-by":"crossref","first-page":"4121","DOI":"10.1002\/jcp.30166","article-title":"The role of toll-like receptor 4 (TLR4) in cancer progression: A possible therapeutic target?","volume":"236","author":"B Kashani","year":"2021","journal-title":"J Cell Physiol"},{"issue":"10","key":"pone.0316102.ref023","doi-asserted-by":"crossref","first-page":"166481","DOI":"10.1016\/j.bbadis.2022.166481","article-title":"Uncovering the source of mitochondrial superoxide in pro-inflammatory macrophages: Insights from immunometabolism","volume":"1868","author":"AM Casey","year":"2022","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"issue":"6640","key":"pone.0316102.ref024","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/41131","article-title":"A human homologue of the Drosophila Toll protein signals activation of adaptive immunity","volume":"388","author":"R Medzhitov","year":"1997","journal-title":"Nature"},{"issue":"7344","key":"pone.0316102.ref025","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/nature09973","article-title":"TLR signalling augments macrophage bactericidal activity through mitochondrial ROS","volume":"472","author":"AP West","year":"2011","journal-title":"Nature"},{"issue":"1","key":"pone.0316102.ref026","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1186\/s40425-019-0726-6","article-title":"Tumor-infiltrating B cells affect the progression of oropharyngeal squamous cell carcinoma via cell-to-cell interactions with CD8(+) T cells.","volume":"7","author":"K Hlad\u00edkov\u00e1","year":"2019","journal-title":"J Immunother Cancer"},{"issue":"6684","key":"pone.0316102.ref027","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/30845","article-title":"Immunology. Licence to kill.","volume":"393","author":"A Lanzavecchia","year":"1998","journal-title":"Nature"},{"key":"pone.0316102.ref028","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1146\/annurev.immunol.23.021704.115839","article-title":"TNF\/TNFR family members in costimulation of T cell responses","volume":"23","author":"TH Watts","year":"2005","journal-title":"Annu Rev Immunol"},{"issue":"6","key":"pone.0316102.ref029","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1111\/j.0300-9475.2004.01517.x","article-title":"B-Lymphocytes activated by CD40 ligand induce an antigen-specific anti-tumour immune response by direct and indirect activation of CD8(+) T-cells.","volume":"60","author":"DS Ritchie","year":"2004","journal-title":"Scand J Immunol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0316102","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T18:46:24Z","timestamp":1737053184000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0316102"}},"subtitle":[],"editor":[{"given":"Luwen","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,1,16]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1,16]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0316102","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,16]]}}}