{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T15:14:36Z","timestamp":1788448476791,"version":"build-2803163510"},"reference-count":36,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T00:00:00Z","timestamp":1649289600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["18K07277 and 21K07203"],"award-info":[{"award-number":["18K07277 and 21K07203"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Aichi Medical University research fund","award":["001"],"award-info":[{"award-number":["001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The expression of programmed death ligand-1 (PD-L1) is controlled by complex mechanisms. The elucidation of the molecular mechanisms of PD-L1 expression is important for the exploration of new insights into PD-1 blockade therapy. Detailed mechanisms of the in situ expression of PD-L1 in tissues of oral squamous cell carcinomas (OSCCs) have not yet been clarified. We examined the mechanisms of PD-L1 expression focusing on the phosphorylation of downstream molecules of epidermal growth factor (EGF) and interferon gamma (IFN-\u03b3) signaling in vitro and in vivo by immunoblotting and multi-fluorescence immunohistochemistry (MF-IHC), respectively. The in vitro experiments demonstrated that PD-L1 expression in OSCC cell lines is upregulated by EGF via the EGF receptor (EGFR)\/PI3K\/AKT pathway, the EGFR\/STAT1 pathway, and the EGFR\/MEK\/ERK pathway, and by IFN-\u03b3 via the JAK2\/STAT1 pathway. MF-IHC demonstrated that STAT1 and EGFR phosphorylation was frequently shown in PD-L1-positive cases and STAT1 phosphorylation was correlated with lymphocyte infiltration and EGFR phosphorylation. Moreover, the phosphorylation pattern of the related molecules in PD-L1-positive cells differed among the cases investigated. These findings indicate that PD-L1 expression mechanisms differ depending on the tissue environment and suggest that the examination of the tissue environment and molecular alterations of cancer cells affecting PD-L1 expression make it necessary for each patient to choose the appropriate combination drugs for PD-1 blockade cancer treatment.<\/jats:p>","DOI":"10.3390\/ijms23084077","type":"journal-article","created":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T13:39:51Z","timestamp":1649338791000},"page":"4077","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["In Situ PD-L1 Expression in Oral Squamous Cell Carcinoma Is Induced by Heterogeneous Mechanisms among Patients"],"prefix":"10.3390","volume":"23","author":[{"given":"Yutaro","family":"Kondo","sequence":"first","affiliation":[{"name":"Department of Maxillofacial Surgery, Aichi Gakuin University School of Dentistry, Nagoya 464-0821, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1466-8824","authenticated-orcid":false,"given":"Susumu","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Research Creation Support Center, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan"},{"name":"Department of Tumor Immunology, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4433-1667","authenticated-orcid":false,"given":"Shoya","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Maxillofacial Surgery, Aichi Gakuin University School of Dentistry, Nagoya 464-0821, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuo","family":"Goto","sequence":"additional","affiliation":[{"name":"Department of Maxillofacial Surgery, Aichi Gakuin University School of Dentistry, Nagoya 464-0821, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Miyabe","sequence":"additional","affiliation":[{"name":"Department of Maxillofacial Surgery, Aichi Gakuin University School of Dentistry, Nagoya 464-0821, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4093-9533","authenticated-orcid":false,"given":"Tetsuya","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromi","family":"Tsuchida","sequence":"additional","affiliation":[{"name":"Research Creation Support Center, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Pathology, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taishi","family":"Takahara","sequence":"additional","affiliation":[{"name":"Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute 480-1195, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Satou","sequence":"additional","affiliation":[{"name":"Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute 480-1195, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4855-4366","authenticated-orcid":false,"given":"Toyonori","family":"Tsuzuki","sequence":"additional","affiliation":[{"name":"Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute 480-1195, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Yoshikawa","sequence":"additional","affiliation":[{"name":"Research Creation Support Center, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuzo","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Tumor Immunology, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Nagao","sequence":"additional","affiliation":[{"name":"Department of Maxillofacial Surgery, Aichi Gakuin University School of Dentistry, Nagoya 464-0821, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5591","DOI":"10.1242\/jcs.116392","article-title":"The Tumor Microenvironment at a Glance","volume":"125","author":"Balkwill","year":"2012","journal-title":"J. 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