PER2 binding to HSP90 enhances immune response against oral squamous cell carcinoma by inhibiting IKK/NF-κB pathway and PD-L1 expression

作者全名："Zhang, Zhiwei; Sun, Deping; Tang, Hong; Ren, Jie; Yin, Shilin; Yang, Kai"

作者地址："[Zhang, Zhiwei; Tang, Hong; Yin, Shilin; Yang, Kai] Chongqing Med Univ, Affiliated Hosp 1, Dept Oral & Maxillofacial Surg, Chongqing, Peoples R China; [Sun, Deping] Chongqing Med Univ, Univ Town Hosp, Dept Otolaryngol Head & Neck Surg, Chongqing, Peoples R China; [Ren, Jie] Chongqing Med Univ, Affiliated Hosp 1, Dept Stomatol, Chongqing, Peoples R China"

通信作者："Yang, K (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Oral & Maxillofacial Surg, Chongqing, Peoples R China."

来源：JOURNAL FOR IMMUNOTHERAPY OF CANCER

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001097766400002

JCR分区：Q1

影响因子：10.3

年份：2023

卷号：11

期号：11

开始页：　

结束页：　

文献类型：Article

关键词：head and neck neoplasms; tumor escape; immunotherapy

摘要："BackgroundProgrammed 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).MethodsQuantitative 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.ResultsIn 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-kappa B 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 IKK alpha/beta and p65 nuclear translocation to inhibit IKK/NF-kappa B 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.ConclusionsOur 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."

基金机构："Chongqing Talents <middle dot> Innovation Leading Talents Project [CQYC20200303128]; Natural Science Foundation of Chongqing, China [cstc2018jcyjAX0208]"

基金资助正文："This study was sponsored by grants from Chongqing Talents <middle dot> Innovation Leading Talents Project (CQYC20200303128 to KY) and Natural Science Foundation of Chongqing, China (cstc2018jcyjAX0208 to KY)."