Nocardia rubra cell-wall skeleton influences the development of cervical carcinoma by promoting the antitumor effect of macrophages and dendritic cells

Cancer Med. 2022 Jan 7. doi: 10.1002/cam4.4526. Online ahead of print.

Abstract

Background: As an immune enhancer, Nocardia rubra cell-wall skeleton (Nr-CWS) has been used to treat persistent human papillomavirus infection and cervical precancerous lesions. However, it is still unclear whether it can be used to treat cervical carcinoma.

Methods: In our study, the aim was to determine whether Nr-CWS affects the apoptosis of cervical carcinoma cells by enhancing the antitumor effect of dendritic cells and macrophages in vivo and in vitro.

Results: The experimental results showed that Nr-CWS can promote the activity of dendritic cells and macrophages and reduce their apoptosis. It also increased the cytokines IL-6, IL-12, TNF-ɑ, and IL-1β secreted by dendritic cells and macrophages and reduced their PD-L1 expression. In vitro, Nr-CWS inhibited the proliferation, colony forming ability of HeLa and SiHa cervical carcinoma cell lines cultured with macrophages, and more cells were blocked in G2/M phase. Nr-CWS promoted TNF-ɑ/TNFR1/caspase-8-mediated apoptosis by increasing macrophages secretion of TNF-ɑ and inhibited cell migration and invasion regulated by the WNT/β-catenin-EMT pathway. Nr-CWS also reduced the expression of the cervical carcinoma genes E6 and E7 thereby increasing expression of p53 gene and decreasing expression of PD-L1 gene. In vivo, Nr-CWS inhibited tumor growth and decreased the expression of E6, E7, PD-L1, P16, Ki67, and PCNA in tumors.

Conclusions: Therefore, our results suggest that Nr-CWS can promote apoptosis of cervical carcinoma cells by enhancing the antitumor effect of dendritic cells and macrophages.

Keywords: Nocardia rubra cell-wall skeleton; cervical carcinoma; dendritic cell; innate immune; macrophage.