Cancer Associated Endogenous Retroviruses: Ideal Immune Targets for Adenovirus-Based Immunotherapy

Abstract

<jats:p>Cancer is a major challenge in our societies, according to the World Health Organization (WHO) about 1/6 deaths were cancer related in 2018 and it is considered the second leading cause of death globally. Immunotherapies have changed the paradigm of oncologic treatment for several cancers where the field had fallen short in providing competent therapies. Despite the improvement, broadly acting and highly effective therapies capable of eliminating or preventing human cancers with insufficient mutated antigens are still missing. Adenoviral vector-based vaccines are a successful tool in the treatment of various diseases including cancer; however, their success has been limited. In this review we discuss the potential of adenovirus as therapeutic tools and the current developments to use them against cancer. More specifically, we examine how to use them to target endogenous retroviruses (ERVs). ERVs, comprising 8% of the human genome, have been detected in several cancers, while they remain silent in healthy tissues. Their low immunogenicity together with their immunosuppressive capacity aid cancer to escape immunosurveillance. In that regard, virus-like-vaccine (VLV) technology, combining adenoviral vectors and virus-like-particles (VLPs), can be ideal to target ERVs and elicit B-cell responses, as well as CD8+ and CD4+ T-cells responses.</jats:p>

Systems Biology to Understand and Regulate Human Retroviral Proinflammatory Response

“…Understanding the role of each HERV in general cellular functions such as growth, cell division, differentiation, and immune responses are vital to reveal the connection of HERVs in human diseases. For example, with the ability to regulate innate response through TLRs and the resultant adaptive immune response through antigens recognition, they could be explored as future agents for cancer immunotherapy ( 62 , 97 ). Furthermore, HERV expressions are mostly silenced by DNA methylation and histone modification.…”

“…There are numerous other links that show the connection or causality between cancer and elevated HERV expressions ( 60 ). Such mounting evidences have led to the development of immunotherapeutic strategies that targets HERVs ( 61 , 62 ). Nevertheless, these methods may not be effective as the detailed mechanistic understanding, such as how the upstream signaling process that activates the downstream distinct HERVs in diverse cancers are still largely unknown.…”

Increased HERV-K(HML-2) Transcript Levels Correlate with Clinical Parameters of Liver Damage in Hepatitis C Patients

“…Studies in recent years have provided compelling evidence that HERVs critically influence genome functions, mainly through transcriptional control [ 12 , 33 ]. They are now suggested as an important force in the genome evolution and adaptation of an organism to altered environmental conditions and have been associated with several diseases, including cancers and neurodegenerative disorders [ 34 , 35 ]. Multiple human HERV-K(HML-2) proviruses encode for the viral genes, pol, gag, and env [ 17 ].…”

A zebrafish reporter line reveals immune and neuronal expression of endogenous retrovirus

“…Aberrant expression of ERVs contributes to multiple pathologies. ERVs are found in abundance in multiple forms of cancers and are considered tumour-promoting factors (extensively reviewed in (Bermejo et al 2020). The pathology of auto-inflammatory diseases has also been strongly associated with ERVs.…”