Nocardia Rubra Cell Wall Skeleton Up-Regulates T Cell Subsets and Inhibits PD-1/PD-L1 Pathway to Promote Local Immune Status of Patients With High-Risk Human Papillomavirus Infection and Cervical Intraepithelial Neoplasia.

Wei Chen,Qianyu Guo,Chunfang Zhao,Xuehui Li,Suxia Shao,Lei Zhang,Yanan Zhang,Yi Zhang,Junmin Tang,Xue Bai,Qianwen Liu

doi:10.3389/fimmu.2020.612547

Abstract

The Nocardia rubra cell wall skeleton (Nr-CWS) for external use is an immune enhancer, which has been widely used in human cervix diseases such as cervical erosion, but the mechanism of Nr-CWS enhancing immunity is still unclear. The purpose of this study was to explore the effect and mechanism of Nr-CWS on the local immune status of cervical tissue in patients with high-risk human papillomavirus (HR-HPV) infection and cervical precancerous lesion, cervical intraepithelial neoplasia (CIN). The recruited patients with HR-HPV infection and CIN were treated with Nr-CWS. The specimens were taken from these patients before and after local application of Nr-CWS respectively. The normal control specimens were tested simultaneously. Serial section analysis of immunohistochemistry and co-expression analysis were performed to characterize populations of T cells and the expressions of programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1). The levels of cytokines in local cervical tissue were also detected. Nr-CWS significantly increased T cells including CD4+, CD8+ T cells, and reduced the expression of PD-L1 in the patients’ local cervical tissues. Co-expression analyses showed that the proportions of PD-1+CD4+ cells in CD4+ T cells and PD-1+CD8+ cells in CD8+ T cells decreased after Nr-CWS application. Furthermore, the increase in the number of immune cells was accompanied by increased pro-inflammatory cytokines interleukin-12 (IL-12), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and decreased suppressive cytokine IL-10. The results indicate that Nr-CWS, as an immunotherapeutic agent for HR-HPV infection and CIN, plays an immune promoting role related to the upregulation of T cell subsets and the inhibition of PD-1/PD-L1 pathway.

Highlights

Cervical cancer is the fourth most common cancer in females worldwide
Age range Mean age1 Subjects infected with HR-human papillomavirus (HPVs) type Single infection Multiple infection high-risk HPV (HR-HPV) overcast rate Pathological features cervical intraepithelial neoplasia (CIN) I CIN II Effective rate in pathological changes
The results showed that the HR-HPV overcast rate was about 60.87% after 3 months of repair, which was higher than the natural HPV negative conversion rate (26.9%) within 3 months [18]

Summary

Introduction

Cervical cancer is the fourth most common cancer in females worldwide. China together with India, contributed more than onethird of the global cervical burden in 2018, with 106,000 cases and 48,000 deaths in China [1]. Cervical cancer is still an important cause of mortality among females in developing countries [2]. Not all women who harbor HPV infection will develop cervical cancer. The risk of CIN increases with the type of HPV, duration of infection, immunosuppression, and environmental factors like cigarette smoking in the patient. The presence of persistent infection with high-risk HPV (HR-HPV) [5] and those who have associated cofactors like immunodeficiency or smoking are at higher risk for the progression of lesions to the development of invasive cancer. In China, the reported HR-HPV persistent infection rate among women (ages 16–69) was 13.30%– 22.94% [6]. It was reported that 21% of patients progressed to CIN 2 or higher, if HR-HPV infection persisted for more than 1 year [7]

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