{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T16:30:24Z","timestamp":1792773024207,"version":"4.5.0"},"reference-count":44,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Oral Diseases"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immune checkpoints such as, LAG\u20103, TIM\u20103, and IDO1 have emerged as potential therapeutic targets beyond PD\u20101\/PD\u2010L1 blockade. Their expression patterns in oral squamous cell carcinoma, especially among patients without smoking or alcohol exposure, remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Immunohistochemical expression of LAG\u20103, TIM\u20103, and IDO1 was examined in 130 oral squamous cell carcinoma specimens. Expression levels were correlated with clinicopathological features, immune infiltration (CD4\n                      <jats:sup>+<\/jats:sup>\n                      , CD8\n                      <jats:sup>+<\/jats:sup>\n                      , FoxP3\n                      <jats:sup>+<\/jats:sup>\n                      , CD1a\n                      <jats:sup>+<\/jats:sup>\n                      ), PD\u20101\/PD\u2010L1 status, and smoking and drinking history. Tumors co\u2010expressing all checkpoints (LAG\u20103\n                      <jats:sup>+<\/jats:sup>\n                      \/TIM\u20103\n                      <jats:sup>+<\/jats:sup>\n                      \/IDO1\n                      <jats:sup>+<\/jats:sup>\n                      \/PD\u2010L1\n                      <jats:sup>+<\/jats:sup>\n                      ) were classified as \u201ccomprehensive checkpoint\u2010positive.\u201d\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      High LAG\u20103, TIM\u20103, and IDO1 expression was significantly associated with never\u2010smoking\/never\u2010drinking status (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009\u2264\u20090.039) and increased CD4\n                      <jats:sup>+<\/jats:sup>\n                      , CD8\n                      <jats:sup>+<\/jats:sup>\n                      , and FoxP3\n                      <jats:sup>+<\/jats:sup>\n                      T\u2010cell densities (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009\u2264\u20090.015). All markers showed strong correlations with PD\u20101\/PD\u2010L1 and with each other (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009\u2264\u20090.002). The comprehensive checkpoint\u2010positive phenotype occurred in 16.8% of cases, more often in never\u2010smoking\/never\u2010drinking patients (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.011), females (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.026), and well\u2010differentiated tumors (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.007).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Co\u2010expression of LAG\u20103, TIM\u20103, and IDO1 characterizes an immune\u2010active but potentially exhausted microenvironment, particularly in never\u2010smoking, never\u2010drinking oral squamous cell carcinoma. This pattern may define an immunologically distinct subtype with possible relevance for combinatorial immunotherapy approaches.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/odi.70301","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T09:12:20Z","timestamp":1773911540000},"page":"2244-2256","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Increased LAG\u20103, TIM\u20103, and IDO1 Expression Is Associated With Oral Squamous Cell Carcinoma in Never Smokers and Never Drinkers"],"prefix":"10.1111","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6822-3089","authenticated-orcid":false,"given":"Mathias","family":"Fiedler","sequence":"first","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery University Hospital Regensburg  Regensburg Germany"},{"name":"Department of Oral and Maxillofacial Surgery, Center for Medical Biotechnology University Hospital Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisa","family":"Off","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery University Hospital Regensburg  Regensburg Germany"},{"name":"Institute of Pathology University of Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Eichberger","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery University Hospital Regensburg  Regensburg Germany"},{"name":"Department of Oral and Maxillofacial Surgery, Center for Medical Biotechnology University Hospital Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Gottsauner","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery University Hospital Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes G.","family":"Schuderer","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery University Hospital Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Maurer","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery University Hospital Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Eckm\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery University Hospital Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Himmelsto\u00df","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery University Hospital Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Bauer","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery University Hospital Regensburg  Regensburg Germany"},{"name":"Institute of Pathology University of Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Gerken","sequence":"additional","affiliation":[{"name":"Center of Tumor Registry University of Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torsten E.","family":"Reichert","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery University Hospital Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Weber","sequence":"additional","affiliation":[{"name":"Institute of Pathology University of Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0549-5351","authenticated-orcid":false,"given":"Tobias","family":"Ettl","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery University Hospital Regensburg  Regensburg Germany"},{"name":"Department of Oral and Maxillofacial Surgery, Center for Medical Biotechnology University Hospital Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aag0299"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.22.02072"},{"issue":"11","key":"e_1_2_11_4_1","first-page":"3282","article-title":"Smoking and Drinking in Relation to Oral and Pharyngeal Cancer","volume":"48","author":"Blot W. 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