title: Increased expression of PD‑L1 by the human papillomavirus 16 E7 oncoprotein inhibits anticancer immunity.
abstract: Cytotoxic T lymphocyte dysfunction is frequently associated with PD‑L1/PD‑1 pathway activation, and is a principal obstacle in cancer therapy. In the present study, the mechanisms underlying the human papillomavirus (HPV)‑induced evasion of cervical cancer cells to the host immune system via the programmed death ligand  1/programmed death 1 (PD‑L1/PD‑1) signaling pathway was investigated. A significant increase in the expression of the HPV16E7 viral protein and PD‑L1 in cervical tissues was observed when compared with normal cervical tissues. In addition, a positive correlation between HPV16E7 and PD‑L1 expression was observed by immunohistochemical staining and reverse transcription‑polymerase chain reaction. Overexpressing HPV16E7 oncoprotein in the epithelial carcinoma of PC3 cells increased the expression level of the PD‑L1 protein and inhibited peripheral blood mononuclear cell (PBMC) proliferation and cytotoxic T lymphocyte (CTL) activity. Upon knockdown of HPV16E7 in HPV16‑associated CaSki cervical cancer cells with a relevant siRNA, a reduction in PD‑L1 protein expression was observed, as well as a significant increase in PBMC proliferation and CTL activity. A recombinant plasmid, MSCVPIG‑soluble PD‑1, was constructed and transfected into the CaSki cell line, and was co‑cultured with PBMCs. PBMC proliferation and CTL activity were observed to increase significantly. In conclusion, the results presented in the current study suggest that overexpression of PD‑L1, induced by HPV16E7, may be responsible for lymphocyte dysfunction. In addition, soluble PD‑1 may restore the function of tumor‑infiltrating lymphocytes by inhibiting the PD‑L1/PD‑1 signaling pathway. These results may provide a novel insight for immunotherapeutic approaches in the treatment of cervical cancer.
authors.affiliation: Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, Hubei 443001, P.R. China.
authors.forename: Chaoqi
authors.initials: C
authors.lastname: Liu
authors.affiliation: Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, Hubei 443001, P.R. China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Lu
authors.affiliation: Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, Hubei 443001, P.R. China.
authors.forename: Huiqun
authors.initials: H
authors.lastname: Tian
authors.affiliation: Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, Hubei 443001, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Du
authors.affiliation: Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, Hubei 443001, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, Hubei 443001, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Feng
authors.affiliation: The Second Clinical Medical College, China Three Gorges University, Yichang, Hubei 443001, P.R. China.
authors.forename: Ding
authors.initials: D
authors.lastname: Yuan
authors.affiliation: The Second Clinical Medical College, China Three Gorges University, Yichang, Hubei 443001, P.R. China.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Li
mesh_terms: D060890:B7-H1 Antigen / Q000235:genetics*; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D052162:Human papillomavirus 16 / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D056747:Immunomodulation; D008213:Lymphocyte Activation; D009369:Neoplasms / Q000209:etiology* / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000209:etiology / Q000378:metabolism
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16