Abstract
The growth of human papillomavirus (HPV)-transformed cells depends on the ability of the viral oncoproteins E6 and E7, especially those from high-risk HPV16/18, to manipulate the signaling pathways involved in cell proliferation, cell death, and innate immunity. Emerging evidence indicates that E6/E7 inhibition reactivates the host innate immune response, reversing what until then was an unresponsive cellular state suitable for viral persistence and tumorigenesis. Given that the disruption of distinct mechanisms of immune evasion is an attractive strategy for cancer therapy, the race is on to gain a better understanding of E6/E7-induced immune escape and cancer progression. Here, we review recent literature on the interplay between E6/E7 and the innate immune signaling pathways cGAS/STING/TBK1, RIG-I/MAVS/TBK1, and Toll-like receptors (TLRs). The overall emerging picture is that E6 and E7 have evolved broad-spectrum mechanisms allowing for the simultaneous depletion of multiple rather than single innate immunity effectors. The cGAS/STING/TBK1 pathway appears to be the most heavily impacted, whereas the RIG-I/MAVS/TBK1, still partially functional in HPV-transformed cells, can be activated by the powerful RIG-I agonist M8, triggering the massive production of type I and III interferons (IFNs), which potentiates chemotherapy-mediated cell killing. Overall, the identification of novel therapeutic targets to restore the innate immune response in HPV-transformed cells could transform the way HPV-associated cancers are treated.
Highlights
Human papillomaviruses (HPVs) are small, non-enveloped double-stranded DNA viruses responsible for the development of cancers of the anogenital and upper aerodigestive tract, with an incidence of ~5% among all cancers worldwide
We summarize a growing body of literature highlighting the biological relevance of E6/E7 as suppressors of the innate immune response in HPV-driven tumorigenesis
We have reviewed past and current literature addressing common strategies evolved by hrHPV genotypes to subvert the innate immune response in keratinocytes and create an unreactive cellular milieu conducive to cell transformation
Summary
Human papillomaviruses (HPVs) are small, non-enveloped double-stranded DNA viruses responsible for the development of cancers of the anogenital and upper aerodigestive tract, with an incidence of ~5% among all cancers worldwide. E6 and E7, the only two viral genes consistently found in cervical tumors, are required for the development of HPV-associated cancer. The transforming activity of these two oncoproteins is mediated primarily through protein–protein interactions conducive to a replication-competent environment that includes the dampening of the innate immune response. The deregulated expression of the two viral oncoproteins E6/E7 is necessary for tumor development and maintenance. In light of the above, this review will provide an overview of recent studies bridging E6/E7-mediated inhibition of innate antiviral immunity and cancer progression. Understanding how the deregulated expression of E6/E7 can efficiently subvert innate and adaptive immunity may pave the way for the development of novel anticancer strategies aimed at restoring cellular reactivity in HPV-transformed cells. We summarize a growing body of literature highlighting the biological relevance of E6/E7 as suppressors of the innate immune response in HPV-driven tumorigenesis
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