Overexpression of programmed cell death ligand 1 in patients with CIN and its correlation with human papillomavirus infection and CIN persistence

Abstract

Backround HPV causes specific cell-mediated immunity in the cervix. Mononuclear cells such as helper T cells (CD4+), cytotoxic T cells (CD8+), and dendritic cells play a critical role in the initiation of the HPV-specific immune response and destruction of virus-infected cervical epithelial cells. The programmed cell death ligand 1 (PD-L1) gene encodes an immune inhibitory receptor ligand and overexpression of PD-L1 inhibits T-cell activation and cytokine production. The aim of this study was to investigate the expression of PD-L1 in cervical tissue and its correlation with clinicopathological findings. Methods In this cross-sectional study, a total of 94 women who were referred for colposcopy due to abnormal Papanicolaou (PAP) test results and/or HPV positivity were evaluated. The presence of HR-HPV–DNA was analyzed using type- and gene-specific primers along with commercial real-time polymerase chain reaction. The cervical examination was done with a colposcope. Cervical biopsies were obtained from the areas that were evaluated as abnormal during the colposcopy. Histopathological result of cervical biopsies were defined as no intraepithelial neoplasia (CIN 0), mild CIN (CIN I), and moderate-to-high CIN (CIN II-III). All women were classified into four groups based on their HR-HPV positivity and cervical biopsy results: Group I (controls; n = 29), HR-HPV (−) CIN 0; Group II ( n = 21), HR-HPV (+) CIN 0; Group III ( n = 20), HR-HPV (+) CIN I; and Group IV ( n = 24), HR-HPV (+) CIN II-III. A semi-quantitative scoring system was used to evaluate the degree of Ki-67, p16, and PD-L1 immunoreactivity in the cervical tissue samples. Results We found that PD-L1 expression in both mononuclear cells and in cervical epithelial cells gradually increases from the HR-HPV (−), CIN 0 group to the HR-HPV (+), CIN II-III group ( p = 0.0003 and p = 0.0394, respectively) and mononuclear PD-L1 expression was correlated with HPV type, initial Pap test results, HPV persistence, and CIN persistence or recurrence ( p = 0.0180, p = 0.0109, p = 0.0042, and p = 0.0189, respectively). Moreover, mononuclear PD-L1 expression was also correlated with Ki-67 and p16 immunoreactivity ( p = 0.0432 and p = 0.0166, respectively). Epithelial PD-L1 expression was only correlated with HPV type and the presence of HPV persistence ( p = 0.0122 and p = 0.0292, respectively). Conclusion During the initial evaluation of the cervical histology results, the assessment of PD-L1 expression—especially in mononuclear cells in cervical tissue samples—may provide more information on the progr...

Immune System Disorders, Cancer and Viral Infections: A New Treatment Opportunity for the Immune Checkpoint Inhibitors

“…This is true not only for already established tumours, but also in precursor lesions. The study conducted by Usta et al showed how the expression of PDL-1 is higher when the degree of dysplasia of cervical epithelial cells is increased, and this expression is related to the presence of HPV infection [33].…”

The Relationship between Furin and Chronic Inflammation in the Progression of Cervical Intraepithelial Neoplasia to Cancer: A Cross-Sectional Study

“…Standardized tissue preparation protocols were followed during the histopathological examination of cervical tissues as previously described [27]. Subsequently, anti-furin (1:100; Santa Cruz Biotechnology Inc., Dallas, TX, USA), anti-ki-67 (1:100; Santa Cruz Biotechnology Inc., Dallas, TX, USA), and anti-p16 (1:50; Santa Cruz Biotechnology Inc., Dallas, TX, USA) antibodies were applied.…”

Cervical Neoplasia: Papillomavirus Infection and Resistance to Anti Tumor Immunity

“…Indeed, the expression of PD-L1 is stronger at the level of the basal layer and of the intraepithelial capillaries due to the presence of T lymphocyte found respectively in the chorion and in the vascular lumen, thus carrying out the phenomenon of empirepolesis [69]. Epithelial cells resistant to this anti-tumor immune mechanism develop PD-L1 on their membrane which binds to lymphocyte PD1 thus generating an immune tolerance system responsible for the progression from intraepithelial neoplasia to cervical cancer [95].…”

“…PD-L1 expression was observed in 81.25% of grade 3 cervical intraepithelial neoplasms in this study. Intraepithelial neoplasms and its correlation with the persistence of human papillomavirus infection, expression of PD-L1 in cervical epithelial and mononuclear cells gradually increases from the CIN 1 group without Papillomavirus positivity to at oncogenic risk towards the oncogenic group CIN II-III positive for highrisk oncogenic papillomavirus with a significant difference between the respective groups (p=0.0003 and p=0.0394) [95]. By evaluating the capacity for recurrence of neoplastic intraepithelial lesions of the cervix after conization by looking for the expression of TPX2 and PD-L1 in cells of the surgical margin, the authors noted that the positive PD-L1 level was significantly higher.…”