title: Increased expression of programmed death (PD)-1 and its ligand PD-L1 correlates with impaired cell-mediated immunity in high-risk human papillomavirus-related cervical intraepithelial neoplasia.
abstract: Impaired local cellular immunity contributes to the pathogenesis of persistent high-risk human papillomavirus (HR-HPV) infection and related cervical intraepithelial neoplasia (CIN), but the underlying molecular mechanisms remain unclear. Recently, the programmed death 1/programmed death 1 ligand (PD-1/PD-L1; CD279/CD274) pathway was demonstrated to play a critical role in attenuating T-cell responses and promoting T-cell tolerance during chronic viral infections. In this study, we examined the expression of PD-1 and PD-L1 on cervical T cells and dendritic cells (DCs), respectively, from 40 women who were HR-HPV-negative (-) or HR-HPV-positive (+) with CIN grades 0, I and II-III. We also measured interferon-γ, interleukin-12 (IL-12) and IL-10 in cervical exudates. The most common HPV type was HPV 16, followed by HPV 18, 33, 51 and 58. PD-1 and PD-L1 expression on cervical T cells and DCs, respectively, was associated with HR-HPV positivity and increased in parallel with increasing CIN grade. The opposite pattern was observed for CD80 and CD86 expression on DCs, which decreased in HR-HPV+ patients in parallel with increasing CIN grade. Similarly, reduced levels of the T helper type 1 cytokines interferon-γ and IL-12 and increased levels of the T helper type 2 cytokine IL-10 in cervical exudates correlated with HR-HPV positivity and CIN grade. Our results suggest that up-regulation of the inhibitory PD-1/PD-L1 pathway may negatively regulate cervical cell-mediated immunity to HPV and contribute to the progression of HR-HPV-related CIN. These results may aid in the development of PD-1/PD-L1 pathway-based strategies for immunotherapy of HR-HPV-related CIN.
authors.affiliation: Department of Gynaecology and Obstetrics, Chinese PLA (People's Liberation Army) General Hospital, Beijing, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Yang
authors.forename: Yan
authors.initials: Y
authors.lastname: Song
authors.forename: Yun-Long
authors.initials: YL
authors.lastname: Lu
authors.forename: Jun-Zhong
authors.initials: JZ
authors.lastname: Sun
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Wang
mesh_terms: D000328:Adult; D018122:B7-1 Antigen / Q000032:analysis; D051940:B7-2 Antigen / Q000032:analysis; D060890:B7-H1 Antigen / Q000032:analysis*; D001706:Biopsy; D016022:Case-Control Studies; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D004797:Enzyme-Linked Immunosorbent Assay; D005122:Exudates and Transudates / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D061809:Human Papillomavirus DNA Tests; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000032:analysis; D016753:Interleukin-10 / Q000032:analysis; D018664:Interleukin-12 / Q000032:analysis; D009367:Neoplasm Staging; D027383:Papillomaviridae / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D030361:Papillomavirus Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis*; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000473:pathology / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000276:immunology* / Q000473:pathology / Q000821:virology
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C497964:CD86 protein, human; C573415:IFNG protein, human; C508609:IL10 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma
keywords: cervical intraepithelial neoplasia; cytokines; human papillomavirus; programmed death-1; programmed death-1 ligand