The HPV viral regulatory mechanism of TLRs and the related treatments for HPV-associated cancers

Abstract

Infection with human papillomavirus (HPV) typically leads to cervical cancer, skin related cancers and many other tumors. HPV is mainly responsible for evading immune tumor monitoring in HPV related cancers. Toll like receptors (TLRs) are particular pattern recognition molecules. When the body is facing immune danger, it can lead to innate and direct adaptive immunity. TLR plays an important role in initiating antiviral immune responses. HPV can affect the expression level of TLR and interfere with TLR related signaling pathways, resulting in sustained viral infection and even carcinogenesis. This paper introduces the HPV virus and HPV related cancers. We discussed the present comprehension of TLR, its expression and signaling, as well as its role in HPV infection. We also provided a detailed introduction to immunotherapy methods for HPV related diseases based on TLR agonists. This will provide insights into methods that support the therapeutic method of HPV related conditions with TLR agonists.

Keywords: TLR agonists; TLR therapy; cancer; human papillomavirus; toll-like receptors.

Figure 1

Immune escape induced by HPV in tumor microenvironment. HPV has a certain interfering effect on CD4/CD8 lymphocyte response and NK cells, and affects tumor cell proliferation. (1) HPV can interfere with the expression of TLR and immune signaling pathways. HPV can downregulate Th1 response by reducing pro-inflammatory cytokines. In addition, Th2 and Treg responses are stimulated by the virus. (2) HPV infection can affect the activity of CD8 T cells and also affect antigen presentation, resulting in reduced expression of TLR and CCR7 on the cell membrane surface. In addition, it also showed upregulation of the expression of CTLA-4 and PD-1 inhibitor molecules (6). (3) HPV has a toxic effect on NK cells, leading to downregulation of HLA and weakening of NK cell activity. (4) HPV promotes changes in cell cycle regulatory genes such as p53 and pRb, leading to tumor cell proliferation and promoting the establishment of tumor chemical microenvironment (7).

Figure 2

(A) Genomic organization of HPV16. (B) In the process of developing toward a malignant phenotype, the HPV DNA genome is usually integrated into the host cell genome. The breakpoints generated by integration can disrupt the virus regions encoding E2, E4, E5, and L2. E6, E7, and LCR are usually preserved, leading to the development of cancer. (C) The functions of the various structures of HPV.

Figure 3

HPV16 infection cycle. The infection cycle of HPV depends on the differentiation process of keratinocytes. The virus can infect keratin in the basal layer of the epithelium, thereby forming cells. And cells can only form in the final differentiated keratin. At this point, the virus particles and virus capsid proteins are assembled together.

Figure 4

The key TLRs, as well as their signal adapters and downstream media, are crucial for TLR signal transduction. HPV can affect the expression of TLR, which is beneficial for sustained viral infection and even carcinogenesis. The CpG motif from HPV E6 can stimulate TLR9. Infection with HPV E6 and E7 inhibits TLR9 transcription. Contrary to the downregulation of TLR9, the TLR3, 5 and 8 pathways are upregulated during HPV infection. The signal transduction initiated by TLR can activate NF- κB Then activate IRF. The activation of IRF can induce IFN - I, which is crucial for the innate immunity of the virus. HPV L1 VLP can directly activate B cells through TLR4 and MyD88 dependent pathways, thereby producing IgG. In the figure, it should be noted that TLR5 and 11, as well as TLR2 and 6, are independent entities, but their pathways are similar.

Figure 5

HPV infects epithelial cells in the cervical mucosa. HPV DNA integrates into the cellular genome when causing cancer.