{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T17:27:16Z","timestamp":1792517236891,"version":"4.5.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP21H03085"],"award-info":[{"award-number":["JP21H03085"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Oropharyngeal squamous cell carcinoma (OPC) associated with high-risk human papillomavirus (HPV), particularly HPV-16, generally shows favorable outcomes yet paradoxically exhibits a high incidence of early lymphatic metastasis. The immune mechanisms underlying this phenomenon remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted an exploratory spatial transcriptomic analysis using the GeoMx Digital Spatial Profiler on formalin-fixed, paraffin-embedded samples from six patients with palatine tonsil-derived OPC. Tumor tissue regions (TTRs) and lymphoid follicular regions (LFRs) were compared according to HPV status and nodal involvement.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In HPV-positive LFRs, pathways related to B-cell apoptosis appeared downregulated, suggesting prolonged B-cell survival and antigen presentation. Metastasis-negative HPV-positive cases displayed a Th2-skewed immune profile in LFRs, with increased na\u00efve B cells, plasma cells, eosinophils, M2 macrophages, and activated mast cells. In contrast, metastasis-positive cases showed increased T cell activation in LFRs and reduced proliferation-related signaling in TTRs. Pathways involving estrogen signaling and bile acid metabolism were also associated with metastatic behavior.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These exploratory findings suggest that peritumoral Th2-biased immunity within lymphoid structures may contribute to restraining lymphatic metastasis in HPV-positive OPC. Spatial transcriptomics may provide a high-resolution framework for investigating tumor\u2013immune interactions and generating hypotheses for future mechanistic and clinical studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2025.1732480","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T05:15:36Z","timestamp":1764134136000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Exploratory spatial transcriptomic profiling of peritumoral Th2 immune polarization in HPV-positive oropharyngeal cancer"],"prefix":"10.3389","volume":"15","author":[{"given":"Naohiro","family":"Wakisaka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makiko","family":"Moriyama-Kita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Kondo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiji","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayoshi","family":"Ueno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Nakanishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhira","family":"Endo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisashi","family":"Sugimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomokazu","family":"Yoshizaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"B1","volume-title":"TNM Classification of Malignant Tumours","author":"Brierley","year":"2017"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2015.61.6995","article-title":"Epidemiology of human papillomavirus-positive head and neck squamous cell carcinoma","volume":"33","author":"Gillison","year":"2015","journal-title":"J Clin Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00603-7","article-title":"HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management","volume":"19","author":"Lechner","year":"2022","journal-title":"Nat Rev Clin Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.28411","article-title":"The interplay between HPV and host immunity in head and neck squamous cell carcinoma","volume":"134","author":"Andersen","year":"2014","journal-title":"Int J Cancer"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.01701","article-title":"Immunological network in head and neck squamous cell carcinoma-A prognostic tool beyond HPV status","volume":"10","author":"Fialov\u00e1","year":"2020","journal-title":"Front Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0144-6","article-title":"Tertiary lymphoid structures in the era of cancer immunotherapy","volume":"19","author":"Saut\u00e8s-Fridman","year":"2019","journal-title":"Nat Rev Cancer"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2931-3","article-title":"Defining HPV-specific B cell responses in patients with head and neck cancer","author":"Wieland","year":"2020","journal-title":"Nature"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0127-6","article-title":"Macrophages as regulators of tumour immunity and immunotherapy","volume":"19","author":"DeNardo","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.840029","article-title":"Metabolic reprogramming induces macrophage polarization in the tumor microenvironment","volume":"13","author":"Wang","year":"2022","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1016\/j.ajpath.2023.04.010","article-title":"Immune-related gene expression profile at peri-tumoral tonsillar tissue is modified by oropharyngeal cancer nodal status","volume":"193","author":"Wakisaka","year":"2023","journal-title":"Am J Pathol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.890410","article-title":"Challenges and opportunities for immunoprofiling using a spatial high-plex technology: the NanoString GeoMx(\u00ae) digital spatial profiler","volume":"12","author":"Hernandez","year":"2022","journal-title":"Front Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1428741","article-title":"Digital Spatial Profiling identifies distinct patterns of immuno-oncology-related gene expression within oropharyngeal tumours in relation to HPV and p16 status","volume":"14","author":"Brooks","year":"2024","journal-title":"Front Oncol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.70207","article-title":"Spatial evidence for carcinoma in situ (CIS) as an entity in human papillomavirus (HPV)-associated tonsillar squamous cell carcinoma (TSCC)","author":"N\u00e4sman","year":"2025","journal-title":"Int J Cancer"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1614498","article-title":"Integrated analysis of single cell and spatial transcriptomics revealed a metastasis mechanism mediated by fatty acid metabolism in lymph nodes of head and neck cancer","volume":"16","author":"Weng","year":"2025","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.anorl.2017.06.002","article-title":"Transoral lateral oropharyngectomy","volume":"134","author":"Rubin","year":"2017","journal-title":"Eur Ann Otorhinolaryngol Head Neck Dis"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0472-9","article-title":"Multiplex digital spatial profiling of proteins and RNA in fixed tissue","volume":"38","author":"Merritt","year":"2020","journal-title":"Nat Biotechnol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: a software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3337","article-title":"Robust enumeration of cell subsets from tissue expression profiles","volume":"12","author":"Newman","year":"2015","journal-title":"Nat Methods"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/ng0506-500","article-title":"GenePattern 2.0","volume":"38","author":"Reich","year":"2006","journal-title":"Nat Genet"},{"key":"B20","doi-asserted-by":"publisher","first-page":"e0144056","DOI":"10.1371\/journal.pone.0144056","article-title":"Primary tumor-secreted lymphangiogenic factors induce pre-metastatic lymphvascular niche formation at sentinel lymph nodes in oral squamous cell carcinoma","volume":"10","author":"Wakisaka","year":"2015","journal-title":"PloS One"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2012.02.003","article-title":"Induction of lymphangiogenesis through vascular endothelial growth factor-C\/vascular endothelial growth factor receptor 3 axis and its correlation with lymph node metastasis in nasopharyngeal carcinoma","volume":"48","author":"Wakisaka","year":"2012","journal-title":"Oral Oncol"},{"key":"B22","doi-asserted-by":"publisher","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":"Wakisaka","year":"2024","journal-title":"PloS One"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2011.36.4596","article-title":"Human papillomavirus and rising oropharyngeal cancer incidence in the United States","volume":"29","author":"Chaturvedi","year":"2011","journal-title":"J Clin Oncol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.oraloncology.2017.05.010","article-title":"Evaluation of type-specific antibodies to high risk-human papillomavirus (HPV) proteins in patients with oropharyngeal cancer","volume":"70","author":"Broglie","year":"2017","journal-title":"Oral Oncol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"3349","DOI":"10.1038\/s41467-021-23355-x","article-title":"B cell signatures and tertiary lymphoid structures contribute to outcome in head and neck squamous cell carcinoma","volume":"12","author":"Ruffin","year":"2021","journal-title":"Nat Commun"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00368","article-title":"NK cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy","volume":"6","author":"Wang","year":"2015","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1922-8","article-title":"B cells and tertiary lymphoid structures promote immunotherapy response","volume":"577","author":"Helmink","year":"2020","journal-title":"Nature"},{"key":"B28","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.tem.2022.11.002","article-title":"Eosinophilia in cancer and its regulation by sex hormones","volume":"34","author":"Artham","year":"2023","journal-title":"Trends Endocrinol Metab"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2021.04.025","article-title":"Eosinophils in health and disease: A state-of-the-art review","volume":"96","author":"Wechsler","year":"2021","journal-title":"Mayo Clin Proc"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.95","article-title":"Functions of tissue-resident eosinophils","volume":"17","author":"Weller","year":"2017","journal-title":"Nat Rev Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2017.00103","article-title":"Bidirectional mast cell-eosinophil interactions in inflammatory disorders and cancer","volume":"4","author":"Galdiero","year":"2017","journal-title":"Front Med (Lausanne)"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.03.012","article-title":"T cell dysfunction in cancer","volume":"33","author":"Thommen","year":"2018","journal-title":"Cancer Cell"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.778258","article-title":"Research progress of bile acids in cancer","volume":"11","author":"Fu","year":"2021","journal-title":"Front Oncol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00568","article-title":"Estrogen signaling modulates allergic inflammation and contributes to sex differences in asthma","volume":"6568","author":"Keselman","year":"2015","journal-title":"Front Immunol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1084\/jem.20080521","article-title":"Estrogen directly activates AID transcription and function","volume":"206","author":"Pauklin","year":"2009","journal-title":"J Exp Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32500","article-title":"Expression of estrogen receptor alpha is associated with pathogenesis and prognosis of human papillomavirus-positive oropharyngeal cancer","author":"Kano","year":"2019","journal-title":"Int J Cancer"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaw1219","article-title":"Slide-seq: A scalable technology for measuring genome-wide expression at high spatial resolution","volume":"363","author":"Rodriques","year":"2019","journal-title":"Science"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1732480\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T05:15:37Z","timestamp":1764134137000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1732480\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,26]]},"references-count":37,"alternative-id":["10.3389\/fonc.2025.1732480"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2025.1732480","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,26]]},"article-number":"1732480"}}