A Systematic Review of Expression and Immunogenicity of Human Endogenous Retroviral Proteins in Cancer and Discussion of Therapeutic Approaches

Mikkel Dons Müller,Peter Johannes Holst,Karen Nørgaard Nielsen

doi:10.3390/ijms23031330

Abstract

Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that have become fixed in the human genome. While HERV genes are typically silenced in healthy somatic cells, there are numerous reports of HERV transcription and translation across a wide spectrum of cancers, while T and B cell responses against HERV proteins have been detected in cancer patients. This review systematically categorizes the published evidence on the expression of and adaptive immune response against specific HERVs in distinct cancer types. A systematic literature search was performed using Medical Search Headings (MeSH) in the PubMed/Medline database. Papers were included if they described the translational activity of HERVs. We present multiple tables that pair the protein expression of specific HERVs and cancer types with information on the quality of the evidence. We find that HERV-K is the most investigated HERV. HERV-W (syncytin-1) is the second-most investigated, while other HERVs have received less attention. From a therapeutic perspective, HERV-K and HERV-E are the only HERVs with experimental demonstration of effective targeted therapies, but unspecific approaches using antiviral and demethylating agents in combination with chemo- and immunotherapies have also been investigated.

Highlights

Checkpoint inhibitor (CPI) therapy has revolutionized cancer treatment
This discrepancy has been suggested to be due to the reactivation of human endogenous retroviruses (HERVs) [9,10] that when translated into proteins are antigenic in a tumor context [11]
Germ cell tumors (GCT) have been known to express HERV proteins for decades [55]. This category includes a number of older publications (Table 1) that primarily used the detection of serum antibodies as a surrogate to detect HERV protein expression [55,56,57,58,59,60]

Summary

Introduction

Checkpoint inhibitor (CPI) therapy has revolutionized cancer treatment. By circumventing inhibitory immune checkpoints induced by tumor cells, CPIs allow for the (re-)activation of otherwise inactive T cells to directly target the tumor cell and have proven effective in otherwise untreatable cancers [1,2]. Prognosis during CPI treatment among different cancers correlates with the tumor mutational burden (TMB) [5] and the presence of cross-presenting dendritic cells [6], corresponding with a prerequisite for cross-presentation of high quality neoantigen epitopes [7]. This trend is consistent across most cancer types, some types exhibit high inflammation and respond to CPI therapy despite a generally low TMB [8]. While some recent reviews focused on the latter [14,15], reviews focused on evidence of HERVs as TAAs are limited

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Discussion

Conclusion