Correlation of E6 and E7 levels in high-risk HPV16 type cervical lesions with CCL20 and Langerhans cells

Abstract

ABSTRACT. The human papillomavirus (HPV)16 E6 and E7 correlation with chemokine ligand (CCL)20 expression and Langerhans cells (LCs) in cervical lesions was investigated. We enrolled 43 patients with surgically treated cervical lesions from the Department of Gynecology in our hospital, and 20 controls without cervical lesions. Subjects were divided by pathology: HPV16(-) and HPV16(+) normal cervical groups (N = 10 each), and HPV16(+) cervical intraepithelial neoplasia (CIN), cervical invasive carcinoma (N = 15 each), and in situ carcinoma (N = 13) groups. E6, E7, the LC surface marker CD1a, and CCL20 were analyzed by immunohistochemistry. E6 and E7 in HPV16-type lesions were correlated with CCL20 and LCs. The average high power field cell numbers of CD1a + LCs in the HPV(-) and HPV(+) normal cervix groups, and the CINI-II, CINIII in situ and cervical carcinoma groups were 22.89 ± 4.84, 13.7 ± 2.26, 9.2 ± 1.68, 5.9 ± 1.59, and 5.5 ± 1.58, respectively. Significant between-group differences existed except between cervical carcinoma and CINIII groups (P < 0.05). CCL20 + rates in each group were 70, 60, 60, 15.38, and 13.33%, respectively. E6/E7-positive expression rates in each group were 20/20, 66.7/66.7, 76.9/69.2, and 86.67/73.3%, respectively. CCL20 was positively correlated with CD1a (r = 0.649), and negatively correlated with E7 (r = -0.946) and E6 (r = -0.949). CD1a was negatively correlated with E6 (r = -0.632) and E7 (r = -0.632). Downregulation of CCL20 leading to LC decline is a key factor in cervical lesions. High-risk HPV-type lesions might inhibit the chemokine CCL20 through E6 and E7 to escape the immune response.

Langerhans cell number is a strong and independent prognostic factor for head and neck squamous cell carcinomas

“…Indeed, we have demonstrated that the expression of MIP-3a in the tumors was significantly associated with the number of LCs in our HNSCC patients. Similar observations have also been demonstrated in several studies of cervical cancer in which the E6 and E7 oncoproteins reduced the expression of MIP-3a in HPV-positive keratinocytes, using qPCR, ELISA, the silencing of E6 and E7 oncogenes (siRNA) and immunohistochemistry, these studies demonstrated decreases in the LC number [30][31][32].…”

Murine HPV16 E7-expressing transgenic skin effectively emulates the cellular and molecular features of human high-grade squamous intraepithelial lesions

“…Dendritic cells represent another population of APCs that may play a role in this setting, but their contributions to the disease is less clear. Two studies reported decrease in CD1a+ DCs classified as immature DCs [73] or CD1a+ Langerhans cells [74] in the cervical stroma and/or epithelium of CIN3 and cancer patients. Other studies reported increase in CD1a+ DCs [50] , or were inconclusive due to variability in their quantification [45] .…”

Modulation of antigen presenting cell functions during chronic HPV infection

“…Furthermore, in vitro experiments revealed that the KC-to-LC interaction mediated by E-cadherin is required for LC differentiation [65] . In HPV16-infected cervical epithelium, E6 and E7 expression and disease severity were correlated with downregulation of CCL20 expression [52] and HPV16 E6 and E7 silencing in vitro promotes CCL20 secretion and LC migration into HPV-infected epithelium [66] . Moreover, in HPV-positive HNSCC patients, immunohistochemical profiling showed that reduced CCL20 expression is correlated with a significant decrease in LC infiltration into tumors [57] .…”

“…HR-HPV positive cancer cells, and E6- and E7-expressing cells can inhibit differentiation of monocytes into LCs in vitro [50] . In cervical precancerous lesions and invasive cancers, active HR-HPV infection and/or expression of E6/E7 oncoproteins were correlated with depletion of intraepithelial LCs [51] , [52] . Similarly, the expression of HPV16 E7 protein alone in murine epidermis has been associated with significantly reduced numbers of epidermal LCs [53] .…”