{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T06:03:27Z","timestamp":1784873007354,"version":"3.55.0"},"reference-count":11,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"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, JP20K21648"],"award-info":[{"award-number":["JP21H03085, JP20K21648"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>In human papillomavirus (HPV)-positive oropharyngeal cancer (OPC), lymph node metastasis is common, yet its biological and prognostic implications remain incompletely understood. Less is known about the spatial organization of immune programs within tumor-associated secondary lymphoid structures.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Immune programs were analyzed by spatially distinguishing lymphoid follicular regions (LFRs) from tumor-free peritumoral tonsillar tissues (PTTs) in palatine tonsil\u2013derived HPV-positive OPC. LFRs were analyzed using spatial transcriptomics and PTTs using bulk transcriptomics. Previously generated GeoMx Digital Spatial Profiler and bulk microarray datasets were reanalyzed to investigate compartment-specific immune programs. Immune pathway activity was assessed using single-sample gene set enrichment analysis according to nodal status.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Compartment-specific immune programs associated with nodal status were identified in both LFRs and PTTs. In LFRs, nodal-positive cases showed enrichment of stem-like, pre-exhausted, and T-cell activity programs accompanied by inflammatory and interferon-associated signaling. In contrast, nodal-negative PTTs exhibited enrichment of stem-like, pre-exhausted, and T-cell activity programs together with IL2\u2013STAT5 and TGF-\u03b2 signaling, without overt inflammatory activation. These findings indicate that identical immune pathways exhibit distinct biological associations depending on their spatial localization.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Immune programs associated with nodal metastasis in HPV-positive OPC vary according to spatial immune context. Distinguishing LFRs from tumor-free PTTs provides a framework for interpreting immune programs beyond bulk tissue analysis and highlights the importance of spatial immune organization in shaping biological interpretation. Because the spatial transcriptomic analyses were performed in a limited number of patients, these findings should be considered exploratory and require validation in larger independent cohorts.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1905992","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T05:36:13Z","timestamp":1784871373000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatial immune programs associated with nodal status differ between lymphoid follicular regions and peritumoral tonsillar tissue in HPV-positive oropharyngeal cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Naohiro","family":"Wakisaka","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology, NHO Kanazawa Medical Center","place":["Kanazawa, Japan"]},{"name":"Division of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medical 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