In Situ PD-L1 Expression in Oral Squamous Cell Carcinoma Is Induced by Heterogeneous Mechanisms among Patients
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 o...
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MDPI AG
2022-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/8/4077 |
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| author | Yutaro Kondo Susumu Suzuki Shoya Ono Mitsuo Goto Satoru Miyabe Tetsuya Ogawa Hiromi Tsuchida Hideaki Ito Taishi Takahara Akira Satou Toyonori Tsuzuki Kazuhiro Yoshikawa Ryuzo Ueda Toru Nagao |
| author_facet | Yutaro Kondo Susumu Suzuki Shoya Ono Mitsuo Goto Satoru Miyabe Tetsuya Ogawa Hiromi Tsuchida Hideaki Ito Taishi Takahara Akira Satou Toyonori Tsuzuki Kazuhiro Yoshikawa Ryuzo Ueda Toru Nagao |
| author_sort | Yutaro Kondo |
| collection | DOAJ |
| description | 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-γ) 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-γ 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. |
| first_indexed | 2024-03-09T10:34:42Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T10:34:42Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-fc62276cf2e046ab94dadf3522f3252b2023-12-01T21:01:41ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-04-01238407710.3390/ijms23084077In Situ PD-L1 Expression in Oral Squamous Cell Carcinoma Is Induced by Heterogeneous Mechanisms among PatientsYutaro Kondo0Susumu Suzuki1Shoya Ono2Mitsuo Goto3Satoru Miyabe4Tetsuya Ogawa5Hiromi Tsuchida6Hideaki Ito7Taishi Takahara8Akira Satou9Toyonori Tsuzuki10Kazuhiro Yoshikawa11Ryuzo Ueda12Toru Nagao13Department of Maxillofacial Surgery, Aichi Gakuin University School of Dentistry, Nagoya 464-0821, JapanResearch Creation Support Center, Aichi Medical University School of Medicine, Nagakute 480-1195, JapanDepartment of Maxillofacial Surgery, Aichi Gakuin University School of Dentistry, Nagoya 464-0821, JapanDepartment of Maxillofacial Surgery, Aichi Gakuin University School of Dentistry, Nagoya 464-0821, JapanDepartment of Maxillofacial Surgery, Aichi Gakuin University School of Dentistry, Nagoya 464-0821, JapanDepartment of Otorhinolaryngology, Aichi Medical University School of Medicine, Nagakute 480-1195, JapanResearch Creation Support Center, Aichi Medical University School of Medicine, Nagakute 480-1195, JapanDepartment of Pathology, Aichi Medical University School of Medicine, Nagakute 480-1195, JapanDepartment of Surgical Pathology, Aichi Medical University Hospital, Nagakute 480-1195, JapanDepartment of Surgical Pathology, Aichi Medical University Hospital, Nagakute 480-1195, JapanDepartment of Surgical Pathology, Aichi Medical University Hospital, Nagakute 480-1195, JapanResearch Creation Support Center, Aichi Medical University School of Medicine, Nagakute 480-1195, JapanDepartment of Tumor Immunology, Aichi Medical University School of Medicine, Nagakute 480-1195, JapanDepartment of Maxillofacial Surgery, Aichi Gakuin University School of Dentistry, Nagoya 464-0821, JapanThe 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-γ) 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-γ 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.https://www.mdpi.com/1422-0067/23/8/4077OSCCoral squamous cell carcinomaEGFepidermal growth factorIFN-γinterferon gamma |
| spellingShingle | Yutaro Kondo Susumu Suzuki Shoya Ono Mitsuo Goto Satoru Miyabe Tetsuya Ogawa Hiromi Tsuchida Hideaki Ito Taishi Takahara Akira Satou Toyonori Tsuzuki Kazuhiro Yoshikawa Ryuzo Ueda Toru Nagao In Situ PD-L1 Expression in Oral Squamous Cell Carcinoma Is Induced by Heterogeneous Mechanisms among Patients International Journal of Molecular Sciences OSCC oral squamous cell carcinoma EGF epidermal growth factor IFN-γ interferon gamma |
| title | In Situ PD-L1 Expression in Oral Squamous Cell Carcinoma Is Induced by Heterogeneous Mechanisms among Patients |
| title_full | In Situ PD-L1 Expression in Oral Squamous Cell Carcinoma Is Induced by Heterogeneous Mechanisms among Patients |
| title_fullStr | In Situ PD-L1 Expression in Oral Squamous Cell Carcinoma Is Induced by Heterogeneous Mechanisms among Patients |
| title_full_unstemmed | In Situ PD-L1 Expression in Oral Squamous Cell Carcinoma Is Induced by Heterogeneous Mechanisms among Patients |
| title_short | In Situ PD-L1 Expression in Oral Squamous Cell Carcinoma Is Induced by Heterogeneous Mechanisms among Patients |
| title_sort | in situ pd l1 expression in oral squamous cell carcinoma is induced by heterogeneous mechanisms among patients |
| topic | OSCC oral squamous cell carcinoma EGF epidermal growth factor IFN-γ interferon gamma |
| url | https://www.mdpi.com/1422-0067/23/8/4077 |
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