The potential role of HPV oncoproteins in the PD-L1/PD-1 pathway in cervical cancer: new perspectives on cervical cancer immunotherapy

Abstract

Cervical cancer (CC) is a common malignant tumour of the female reproductive system that is highly harmful to women's health. The efficacy of traditional surgery, radiotherapy and chemotherapy is limited, especially for recurrent and metastatic CC. With continuous progress in diagnostic and treatment technology, immunotherapy has become a new approach for treating CC and has become a new therapy for recurrent and metastatic CC. However, immunotherapy is not effective for all patients with CC. Therefore, factors related to immunotherapy efficacy in CC patients have become the focus of researchers. High-risk human papillomavirus (HPV) infection is an important factor that drives CC development and affects its progression and prognosis. Increasing attention has been given to the mechanism of the E5, E6 and E7 proteins, which are encoded by the HPV gene, in the occurrence and development of CC and their interaction with programmed cell death ligand-1/programmed cell death-1 (PD-L1/PD-1). Although some preliminary studies have been conducted on these topics, a comprehensive and systematic review of these topics is not available. This review comprehensively summarizes related articles from journals with impact factors greater than 3 and published in the past 5 years; it also reviews studies on the mechanism of HPV and CC, the mechanism of PD-L1/PD-1 axis regulation in CC, and the mechanism by which the interaction between HPV-related oncoproteins and the PD-L1/PD-1 pathway affects the development and prognosis of CC. This study provides theoretical support for the use of immunotherapies for CC, provides a basis for the selection of specific medications that target different HPV-related proteins, and provides a new perspective for the discovery of new immunotherapy targets for CC.

Keywords: HPV oncoproteins; PD-L1/PD-1 pathway; cervical cancer; immunotherapy; regulators.

Figure 1

Interactions between HPV oncoproteins and PD-L1/PD-1 in CC patients. In the tumour microenvironment, the interaction between PD-1 and PD-L1 results in the secretion of inhibitory signals and induces T-cell apoptosis. Blocking this pathway is beneficial for activating T cells, reshaping the tumour microenvironment, and preventing immune escape.

Figure 2

Three major oncoproteins (E5, E6 and E7) affect multiple potential targets involved in the progression of cervical cancer. E5 upregulates EGFR, thereby regulating the expression of COX2 and VEGF; E6 also affects the EGFR pathway by upregulating the expression of JUK1/2 and c-Jun/AP1. In addition, E6 upregulates OCT4/E6AP, and E6 and E7 upregulate HIF1A-AS2, TBX3, IL-2R and miR-18a/34a. OCT4/E6AP and HIF1A-AS2 both affect p53. In addition, E6 and E7 inhibit PIPOR2 and miR-424, whereas E7 upregulates the expression of PKM2, ultimately regulating the progression of cervical cancer.

Figure 3

The pathways through which HPV affects the levels of PD-L1/PD-1 in CC include the YAP, HIF-1, Wnt/β-catenin, JAK-STAT, MAPK, c-GAS, PI3K/AKT, and STING-TBK1 pathways. These pathways are involved mainly in promoting PD-L1 mRNA expression. HPV oncoproteins are positive regulators of these downstream factors, except Memo-1, whose expression is downregulated by E7. E6 and E7 inhibit the expression of miR-142-5p, upregulate the expression of PD-L1, and induce the expression of PD-L1. In addition, the upregulation of METTL3 by HPV can increase the expression of PD-L1.