{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:01:08Z","timestamp":1790834468728,"version":"4.1.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Oral squamous cell carcinoma (OSCC) is the most prevalent form of oral cancer and is characterized by a poor prognosis and frequent immune evasion. While the tumor microenvironment (TME) plays a central role in modulating responses to therapy, its relationship with systemic immune signatures remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed high-dimensional immune profiling in matched peripheral blood, adjacent non-neoplastic peritumor mucosa, and tumor tissue from Human Papillomavirus (HPV)-negative, treatment-na\u00efve patients with advanced OSCC. Soluble mediators were quantified by multiplex immunoassay, and immune cell phenotypes were assessed by multiparametric flow cytometry. Compartment-specific patterns were evaluated using paired and unpaired comparisons, dimensionality reduction, ordinal trend analysis, unsupervised clustering, and correlation networks.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Seventeen plasma mediators were significantly elevated in OSCC patients compared with healthy donors. Paired cellular profiling identified compartment-specific differences across blood, peritumor and tumor, and selected PD-1\n                      <jats:sup>+<\/jats:sup>\n                      CD95\n                      <jats:sup>+<\/jats:sup>\n                      , CD25\n                      <jats:sup>+<\/jats:sup>\n                      FoxP3\n                      <jats:sup>+<\/jats:sup>\n                      , and PD-L1\n                      <jats:sup>+<\/jats:sup>\n                      populations showed significant progressive trends along the blood-peritumor-tumor axis. CD4\n                      <jats:sup>+<\/jats:sup>\n                      mucosal-associated invariant T (MAIT)-like cells (TCR V\u03b17.2\n                      <jats:sup>+<\/jats:sup>\n                      CD161\n                      <jats:sup>+<\/jats:sup>\n                      ) were relatively enriched in peritumor tissue, but the peritumor compartment was not uniformly intermediate across all populations. Correlation networks showed limited overlaps, with greater overlap between peritumor and tumor networks than between either tissue compartment and blood. Plasma profiling showed elevated pro-inflammatory cytokines, chemokines, and growth factors, consistent with systemic immune activation. Peripheral blood exhibited an activated phenotype with increased frequencies of activated T and NK cells, alongside CD4\n                      <jats:sup>-<\/jats:sup>\n                      CD8\n                      <jats:sup>-<\/jats:sup>\n                      TCR V\u03b17.2\n                      <jats:sup>+<\/jats:sup>\n                      CD161\n                      <jats:sup>+<\/jats:sup>\n                      cells. In contrast, the tumor microenvironment was enriched for CD95\n                      <jats:sup>+<\/jats:sup>\n                      PD-1\n                      <jats:sup>+<\/jats:sup>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells, NK cells and PD-L1\n                      <jats:sup>+<\/jats:sup>\n                      monocytes and CD4\n                      <jats:sup>+<\/jats:sup>\n                      MAIT-like cells. The peritumor compartment showed a distinct immune profile marked by regulatory T cell accumulation and other immunosuppressive mediators, rather than a uniform intermediate state between blood and tumor. Correlation networks revealed pronounced shifts in immune coordination across compartments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Advanced OSCC is associated with distinct systemic and tissue immune profiles. These exploratory findings identify compartment-specific immune features and selected monotonic trends that warrant future spatial, functional, and clinical validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1923358","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:41:43Z","timestamp":1790833303000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Systemic immune activation coexists with compartment-specific regulatory enrichment in matched blood, peritumor, and tumor tissue from advanced oral squamous cell carcinoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Nayane Alves de Lima","family":"Galdino","sequence":"first","affiliation":[{"name":"Translational Immuno-Oncology Group, International Research Center, A.C.Camargo Cancer Center","place":["S\u00e3o Paulo, SP, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fl\u00e1vio","family":"Pignataro-Oshiro","sequence":"additional","affiliation":[{"name":"Translational Immuno-Oncology Group, International Research Center, A.C.Camargo Cancer Center","place":["S\u00e3o Paulo, SP, Brazil"]},{"name":"Translational Immuno-Oncology Laboratory, Faculdade Israelita de Ci\u00eancias da Sa\u00fade Albert Einstein, Hospital Israelita Albert Einstein","place":["S\u00e3o Paulo, SP, Brazil"]},{"name":"Center for Research in Immuno-Oncology (CRIO), Faculdade Israelita de Ci\u00eancias da Sa\u00fade Albert Einstein, Hospital Israelita Albert Einstein","place":["S\u00e3o Paulo, SP, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o Figueira","family":"Scarini","sequence":"additional","affiliation":[{"name":"Translational Immuno-Oncology Laboratory, Faculdade Israelita de Ci\u00eancias da Sa\u00fade Albert Einstein, Hospital Israelita Albert Einstein","place":["S\u00e3o Paulo, SP, Brazil"]},{"name":"Center for Research in Immuno-Oncology (CRIO), Faculdade Israelita de Ci\u00eancias da Sa\u00fade Albert Einstein, Hospital Israelita Albert Einstein","place":["S\u00e3o Paulo, SP, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ra\u00edsa","family":"Sales de S\u00e1","sequence":"additional","affiliation":[{"name":"Translational Immuno-Oncology Laboratory, Faculdade Israelita de Ci\u00eancias da Sa\u00fade Albert Einstein, Hospital Israelita Albert Einstein","place":["S\u00e3o Paulo, SP, Brazil"]},{"name":"Center for Research in Immuno-Oncology (CRIO), Faculdade Israelita de Ci\u00eancias da Sa\u00fade Albert Einstein, Hospital Israelita Albert Einstein","place":["S\u00e3o Paulo, SP, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guilherme Ferreira de Britto","family":"Evangelista","sequence":"additional","affiliation":[{"name":"Translational Immuno-Oncology Group, International Research Center, A.C.Camargo Cancer Center","place":["S\u00e3o Paulo, SP, Brazil"]},{"name":"Translational Immuno-Oncology Laboratory, Faculdade Israelita de Ci\u00eancias da Sa\u00fade Albert Einstein, Hospital Israelita Albert Einstein","place":["S\u00e3o Paulo, SP, Brazil"]},{"name":"Center for Research in Immuno-Oncology (CRIO), Faculdade Israelita de Ci\u00eancias da Sa\u00fade Albert Einstein, Hospital Israelita Albert Einstein","place":["S\u00e3o Paulo, SP, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda Braga","family":"Figueiredo","sequence":"additional","affiliation":[{"name":"Translational Immuno-Oncology Group, International Research Center, A.C.Camargo Cancer Center","place":["S\u00e3o Paulo, SP, Brazil"]},{"name":"Translational Immuno-Oncology Laboratory, Faculdade Israelita de Ci\u00eancias da Sa\u00fade Albert Einstein, Hospital Israelita Albert Einstein","place":["S\u00e3o Paulo, SP, Brazil"]},{"name":"Center for Research in Immuno-Oncology (CRIO), Faculdade Israelita de Ci\u00eancias da Sa\u00fade Albert Einstein, Hospital Israelita Albert Einstein","place":["S\u00e3o Paulo, SP, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara Maciel","family":"Cavalcanti","sequence":"additional","affiliation":[{"name":"Center for Research in Immuno-Oncology (CRIO), Faculdade Israelita de Ci\u00eancias da Sa\u00fade Albert Einstein, Hospital Israelita Albert Einstein","place":["S\u00e3o Paulo, SP, Brazil"]},{"name":"Flow Cytometry Core Facility, Memorial Sloan-Kettering Cancer Center","place":["New York, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia Luciano Pereira","family":"Morais","sequence":"additional","affiliation":[{"name":"Translational Immuno-Oncology Group, International Research Center, A.C.Camargo Cancer Center","place":["S\u00e3o Paulo, SP, Brazil"]},{"name":"Translational Immuno-Oncology Laboratory, Faculdade Israelita de Ci\u00eancias da Sa\u00fade Albert Einstein, Hospital Israelita Albert Einstein","place":["S\u00e3o Paulo, SP, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa Alves","family":"Gasparini","sequence":"additional","affiliation":[{"name":"International Research Center, A.C.Camargo Cancer Center","place":["S\u00e3o Paulo, SP, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo Fontan","family":"Kohler","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Head and Neck Cancer Reference Center, A.C.Camargo Cancer Center","place":["S\u00e3o Paulo, SP, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiago","family":"Bueno de Oliveira","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Head and Neck Cancer Reference Center, A.C.Camargo Cancer Center","place":["S\u00e3o Paulo, SP, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiz Paulo","family":"Kowalski","sequence":"additional","affiliation":[{"name":"Department of Head and Neck Surgery and Otorhinolaryngology, A.C.Camargo Cancer Center","place":["S\u00e3o Paulo, SP, Brazil"]},{"name":"Head and Neck Surgery Department, Medical School, University of S\u00e3o Paulo","place":["S\u00e3o Paulo, SP, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth J.","family":"Gollob","sequence":"additional","affiliation":[{"name":"Translational Immuno-Oncology Group, International Research Center, A.C.Camargo Cancer Center","place":["S\u00e3o Paulo, SP, Brazil"]},{"name":"Translational Immuno-Oncology Laboratory, Faculdade Israelita de Ci\u00eancias da Sa\u00fade Albert Einstein, Hospital Israelita Albert Einstein","place":["S\u00e3o Paulo, SP, Brazil"]},{"name":"Center for Research in Immuno-Oncology (CRIO), Faculdade Israelita de Ci\u00eancias da Sa\u00fade Albert Einstein, Hospital Israelita Albert Einstein","place":["S\u00e3o Paulo, SP, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/s41368-023-00249-w","article-title":"Oral squamous cell carcinomas: State of the field and emerging directions","volume":"15","author":"Tan","year":"2023","journal-title":"Int J Oral Sci"},{"key":"B2","doi-asserted-by":"crossref","DOI":"10.5772\/intechopen.99236","article-title":"Oral cancer: Epidemiology, prevention, early detection, and treatment","volume-title":"Oral Cancer - Current Concepts and Future Perspectives","author":"Khani Jeihooni","year":"2022"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2011.04.018","article-title":"A population-based study of factors associated with early versus late stage oral cavity cancer diagnoses","volume":"47","author":"Groome","year":"2011","journal-title":"Oral Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1602252","article-title":"Nivolumab for recurrent squamous-cell carcinoma of the head and neck","volume":"375","author":"Ferris","year":"2016","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e389810","DOI":"10.1200\/EDBK_389810","article-title":"Current treatment strategies and risk stratification for oral carcinoma","volume":"43","author":"Mohamad","year":"2023","journal-title":"Am Soc Clin Oncol Educ Book"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.disamonth.2020.101036","article-title":"Novel therapies in the management of oral cancer: An update","volume":"66","author":"Nandini","year":"2020","journal-title":"Disease-a-Month"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12071937","article-title":"Immune checkpoint inhibitors in oral cavity squamous cell carcinoma and oral potentially malignant disorders: A systematic review","volume":"12","author":"Kujan","year":"2020","journal-title":"Cancers"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2020.105038","article-title":"Tumor microenvironment and oral squamous cell carcinoma: A crosstalk between the inflammatory state and tumor cell migration","volume":"112","author":"Alves","year":"2021","journal-title":"Oral Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.622161","article-title":"Increased tumor immune microenvironment CD3+ and CD20+ lymphocytes predict a better prognosis in oral tongue squamous cell carcinoma","volume":"8","author":"Sales de S\u00e1","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1186\/s12935-023-02943-5","article-title":"Targeting oral tumor microenvironment for effective therapy","volume":"23","author":"Budi","year":"2023","journal-title":"Cancer Cell Int"},{"key":"B11","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of cancer: New dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.844142","article-title":"Immunotherapy: Reshape the tumor immune microenvironment","volume":"13","author":"Lv","year":"2022","journal-title":"Front Immunol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1056\/NEJMoa2415434","article-title":"Neoadjuvant and adjuvant pembrolizumab in locally advanced head and neck cancer","volume":"393","author":"Uppaluri","year":"2025","journal-title":"N Engl J Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.18.00684","article-title":"Human papillomavirus testing in head and neck carcinomas: ASCO clinical practice guideline endorsement of the College of American Pathologists guideline","volume":"36","author":"Fakhry","year":"2018","journal-title":"J Clin Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.5858\/arpa.2017-0286-CP","article-title":"Human papillomavirus testing in head and neck carcinomas: Guideline from the College of American Pathologists","volume":"142","author":"Lewis","year":"2018","journal-title":"Arch Pathol Lab Med"},{"key":"B16","volume-title":"International Classification of Diseases for Oncology","author":"Fritz","year":"2013"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.05.047","article-title":"Data-driven phenotypic dissection of AML reveals progenitor-like cells that correlate with prognosis","volume":"162","author":"Levine","year":"2015","journal-title":"Cell"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.21105\/joss.00861","article-title":"UMAP: Uniform manifold approximation and projection","volume":"3","author":"McInnes","year":"2018","journal-title":"J Open Source Software"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv468","article-title":"ClustVis: A web tool for visualizing clustering of multivariate data using principal component analysis and heatmap","volume":"43","author":"Metsalu","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01721","article-title":"The evolving landscape of PD-1\/PD-L1 pathway in head and neck cancer","volume":"11","author":"Qiao","year":"2020","journal-title":"Front Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2025.104672","article-title":"Immunotherapy in OSCC: Current trend and challenges","volume":"209","author":"Gupta","year":"2025","journal-title":"Crit Rev Oncology\/Hematology"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoto.2013.5688","article-title":"Serum biomarkers in head and neck squamous cell cancer","volume":"140","author":"Kaskas","year":"2014","journal-title":"JAMA Otolaryngology\u2013Head Neck Surg"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3390\/jcm11185398","article-title":"The assessment of serum cytokines in oral squamous cell carcinoma patients: An observational prospective controlled study","volume":"11","author":"Caruntu","year":"2022","journal-title":"J Clin Med"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00585","article-title":"Plasma-derived inflammatory proteins predict oral squamous cell carcinoma","volume":"8","author":"Liu","year":"2018","journal-title":"Front Oncol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13071502","article-title":"MAIT cells: Partners or enemies in cancer immunotherapy","volume":"13","author":"Cogswell","year":"2021","journal-title":"Cancers"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1669","DOI":"10.1038\/s41467-021-21928-4","article-title":"Circulating mucosal-associated invariant T cells identify patients responding to anti-PD-1 therapy","volume":"12","author":"De Biasi","year":"2021","journal-title":"Nat Commun"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15061650","article-title":"Role and potential of different T helper cell subsets in adoptive cell therapy","volume":"15","author":"Andreu-Sanz","year":"2023","journal-title":"Cancers"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2014.01.011","article-title":"Inter-relation of Th1, Th2, Th17 and Treg cytokines in oral cancer patients and their clinical significance","volume":"75","author":"Gaur","year":"2014","journal-title":"Hum Immunol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.oraloncology.2017.03.006","article-title":"Programmed death ligand 1 (PD-L1) expression and tumor microenvironment: Implications for patients with oral precancerous lesions","volume":"68","author":"Yagyuu","year":"2017","journal-title":"Oral Oncol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.741013","article-title":"TNF\u03b1 signaling is increased in progressing oral potentially malignant disorders and regulates malignant transformation in an oral carcinogenesis model","volume":"11","author":"Chadwick","year":"2021","journal-title":"Front Oncol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1158\/1940-6207.CAPR-21-0047","article-title":"Oral squamous cell carcinoma associated with precursor lesions","volume":"14","author":"McCord","year":"2021","journal-title":"Cancer Prev Res"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10081840","article-title":"T-cell infiltration and immune checkpoint expression increase in oral cavity premalignant and malignant disorders","volume":"10","author":"Surendran","year":"2022","journal-title":"Biomedicines"},{"key":"B33","doi-asserted-by":"publisher","first-page":"e70090","DOI":"10.3322\/caac.70090","article-title":"Global cancer statistics 2024: GLOBOCAN estimates of incidence and mortality worldwide for 34 cancers in 186 countries","volume":"76","author":"Sung","year":"2026","journal-title":"CA Cancer J Clin"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1923358\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:41:45Z","timestamp":1790833305000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1923358\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":33,"alternative-id":["10.3389\/fimmu.2026.1923358"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1923358","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]},"article-number":"1923358"}}