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PER2 binding to HSP90 enhances immune response against oral squamous cell carcinoma by inhibiting IKK/NF-κB pathway and PD-L1 expression
BACKGROUND: Programmed death-ligand 1 (PD-L1) contributes to the immune escape of tumor cells and is a critical target for antitumor immunotherapy. However, the molecular mechanisms regulating PD-L1 expression remain unclear, hindering the development of effective therapies. Here we investigate the...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10626827/ https://www.ncbi.nlm.nih.gov/pubmed/37914384 http://dx.doi.org/10.1136/jitc-2023-007627 |
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author | Zhang, Zhiwei Sun, Deping Tang, Hong Ren, Jie Yin, Shilin Yang, Kai |
author_facet | Zhang, Zhiwei Sun, Deping Tang, Hong Ren, Jie Yin, Shilin Yang, Kai |
author_sort | Zhang, Zhiwei |
collection | PubMed |
description | BACKGROUND: Programmed death-ligand 1 (PD-L1) contributes to the immune escape of tumor cells and is a critical target for antitumor immunotherapy. However, the molecular mechanisms regulating PD-L1 expression remain unclear, hindering the development of effective therapies. Here we investigate the role and molecular mechanism of the core clock gene Period2 (PER2) in regulating PD-L1 expression and its role in the combination therapy of oral squamous cell carcinoma (OSCC). METHODS: Quantitative real-time PCR, western blotting or immunohistochemistry to detect expression of PER2 and PD-L1 in OSCC tissues and cells. Overexpression and knockdown of PER2 detects the function of PER2. Bioinformatics, immunoprecipitation, GST pull-down, CHX chase assay and western blot and strip to detect the mechanism of PER2 regulation for PD-L1. A humanized immune reconstitution subcutaneous xenograft mouse model was established to investigate the combination therapy efficacy. RESULTS: In OSCC tissues and cells, PER2 expression was reduced and PD-L1 expression was increased, the expression of PER2 was significantly negatively correlated with PD-L1. In vitro and in vivo experiments demonstrated that PER2 inhibited PD-L1 expression and enhanced T-cell-mediated OSCC cell killing by suppressing the IKK/NF-κB pathway. Mechanistically, PER2 binds to heat shock protein 90 (HSP90) through the PAS1 domain and reduces the interaction of HSP90 with inhibitors of kappa B kinase (IKKs), promoting the ubiquitination of IKKα/β and p65 nuclear translocation to inhibit IKK/NF-κB pathway, thereby suppressing PD-L1 expression. In humanized immune reconstitution subcutaneous xenograft mouse model, it was demonstrated that PER2 targeting combined with anti-PD-L1 treatment improved the inhibition of OSCC growth by promoting CD8(+) T-cell infiltration into the tumor. CONCLUSIONS: Our findings reveal the role and mechanism of PD-L1 regulation by PER2 and support the potential clinical application of PER2 targeting in combination with anti-PD-L1 in OSCC immunotherapy. |
format | Online Article Text |
id | pubmed-10626827 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-106268272023-11-07 PER2 binding to HSP90 enhances immune response against oral squamous cell carcinoma by inhibiting IKK/NF-κB pathway and PD-L1 expression Zhang, Zhiwei Sun, Deping Tang, Hong Ren, Jie Yin, Shilin Yang, Kai J Immunother Cancer Clinical/Translational Cancer Immunotherapy BACKGROUND: Programmed death-ligand 1 (PD-L1) contributes to the immune escape of tumor cells and is a critical target for antitumor immunotherapy. However, the molecular mechanisms regulating PD-L1 expression remain unclear, hindering the development of effective therapies. Here we investigate the role and molecular mechanism of the core clock gene Period2 (PER2) in regulating PD-L1 expression and its role in the combination therapy of oral squamous cell carcinoma (OSCC). METHODS: Quantitative real-time PCR, western blotting or immunohistochemistry to detect expression of PER2 and PD-L1 in OSCC tissues and cells. Overexpression and knockdown of PER2 detects the function of PER2. Bioinformatics, immunoprecipitation, GST pull-down, CHX chase assay and western blot and strip to detect the mechanism of PER2 regulation for PD-L1. A humanized immune reconstitution subcutaneous xenograft mouse model was established to investigate the combination therapy efficacy. RESULTS: In OSCC tissues and cells, PER2 expression was reduced and PD-L1 expression was increased, the expression of PER2 was significantly negatively correlated with PD-L1. In vitro and in vivo experiments demonstrated that PER2 inhibited PD-L1 expression and enhanced T-cell-mediated OSCC cell killing by suppressing the IKK/NF-κB pathway. Mechanistically, PER2 binds to heat shock protein 90 (HSP90) through the PAS1 domain and reduces the interaction of HSP90 with inhibitors of kappa B kinase (IKKs), promoting the ubiquitination of IKKα/β and p65 nuclear translocation to inhibit IKK/NF-κB pathway, thereby suppressing PD-L1 expression. In humanized immune reconstitution subcutaneous xenograft mouse model, it was demonstrated that PER2 targeting combined with anti-PD-L1 treatment improved the inhibition of OSCC growth by promoting CD8(+) T-cell infiltration into the tumor. CONCLUSIONS: Our findings reveal the role and mechanism of PD-L1 regulation by PER2 and support the potential clinical application of PER2 targeting in combination with anti-PD-L1 in OSCC immunotherapy. BMJ Publishing Group 2023-11-01 /pmc/articles/PMC10626827/ /pubmed/37914384 http://dx.doi.org/10.1136/jitc-2023-007627 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Clinical/Translational Cancer Immunotherapy Zhang, Zhiwei Sun, Deping Tang, Hong Ren, Jie Yin, Shilin Yang, Kai PER2 binding to HSP90 enhances immune response against oral squamous cell carcinoma by inhibiting IKK/NF-κB pathway and PD-L1 expression |
title | PER2 binding to HSP90 enhances immune response against oral squamous cell carcinoma by inhibiting IKK/NF-κB pathway and PD-L1 expression |
title_full | PER2 binding to HSP90 enhances immune response against oral squamous cell carcinoma by inhibiting IKK/NF-κB pathway and PD-L1 expression |
title_fullStr | PER2 binding to HSP90 enhances immune response against oral squamous cell carcinoma by inhibiting IKK/NF-κB pathway and PD-L1 expression |
title_full_unstemmed | PER2 binding to HSP90 enhances immune response against oral squamous cell carcinoma by inhibiting IKK/NF-κB pathway and PD-L1 expression |
title_short | PER2 binding to HSP90 enhances immune response against oral squamous cell carcinoma by inhibiting IKK/NF-κB pathway and PD-L1 expression |
title_sort | per2 binding to hsp90 enhances immune response against oral squamous cell carcinoma by inhibiting ikk/nf-κb pathway and pd-l1 expression |
topic | Clinical/Translational Cancer Immunotherapy |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10626827/ https://www.ncbi.nlm.nih.gov/pubmed/37914384 http://dx.doi.org/10.1136/jitc-2023-007627 |
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