Endogenous retroviruses in the origins and treatment of cancer

Abstract

Endogenous retroviruses (ERVs) are emerging as promising therapeutic targets in cancer. As remnants of ancient retroviral infections, ERV-derived regulatory elements coordinate expression from gene networks, including those underpinning embryogenesis and immune cell function. ERV activation can promote an interferon response, a phenomenon termed viral mimicry. Although ERV expression is associated with cancer, and provisionally with autoimmune and neurodegenerative diseases, ERV-mediated inflammation is being explored as a way to sensitize tumors to immunotherapy. Here we review ERV co-option in development and innate immunity, the aberrant contribution of ERVs to tumorigenesis, and the wider biomedical potential of therapies directed at ERVs.

Fig. 1

Human transposable elements. a HERV-K, AluYa5, SVA_F and L1HS (L1 human-specific) are the youngest human ERV, Alu, SVA, and L1 families, respectively. New retrotransposition events are flanked by hallmark target site duplications (TSDs, pink triangles). HERV-K is ~9 kbp in length, contains a tRNA reverse transcription primer binding site (PBS), and encodes overlapping Gag, Pro, Pol, and Env ORFs. Amongst other features, Pol incorporates reverse transcriptase (RT), ribonuclease H (RH), and integrase (IN) activities. AluYa5 (~ 280 bp) is composed of left (L) and right (R) monomers divided by an adenosine-rich region and is followed by a polyadenine tail (A_n). SVA_F (~2 kbp) is a composite element that brings together a variable number of CCCTCT hexamers, an Alu-like sequence, a variable number tandem repeat (VNTR) region and SINE-R, a sequence strongly resembling a portion of the HERV-K Env gene and 3′ LTR. L1HS (~6 kbp) is the only autonomously mobile human TE. It encodes two sense ORFs (ORF1 and ORF2) and an antisense ORF (ORF0) that may boost its mobility [29]. ORF2p possesses endonuclease (EN) and reverse transcriptase (RT) activities. Black arrows indicate known promoter elements. Elements are not depicted to scale. b HERV family statistics [–32]. c HERV retrotransposition model, adapted from [33]. A provirus mRNA is transcribed and translated into a Gag-Pro-Pol fusion protein. Gag is cleaved by Pro to generate a virus-like particle, containing the fusion protein and ERV mRNA. A specific tRNA binds the primer binding site (PBS) to promote reverse transcription, producing a cDNA. The cDNA forms a complex with integrase (IN) to integrate into a new genomic site. d Internal homologous recombination events can occur between 5′ and 3′ LTRs, resulting in loss of the provirus internal region and one LTR, to generate a solo LTR. e Long- and short-read sequencing approaches differ in their ability to discriminate HERV proviral and solo LTR alleles

Fig. 2

ERV regulatory element co-option. a An upstream MER21A LTR provides an alternative placenta-specific promoter to CYP19A1 [15]. b A HERV-K solo LTR (LTR5Hs) enhancer located in the first intron of F11R [10]. c AIM2 expression is enhanced by an adjacent MER41E LTR [16]. Note: each panel displays, from top to bottom, the first exon of a protein-coding gene, the position of an adjacent regulatory LTR, transcriptome (a) or histone modification (b,c) sequencing data, and a magnified view of relevant transcription factor binding sites in each LTR. Histone modification (H3K4me1, H3K4me3, and H3K27ac) profiles were obtained from ENCODE via the UCSC Genome Browser [2]. Transcriptome data in the form of cap analysis gene expression (CAGE) reads generated by the FANTOM consortium were visualized using the ZENBU genome browser [91]

Fig. 3

ERVs contribute to oncogenesis and may be targeted therapeutically. a Onco-exapted ERVs can regulate host gene expression in tumors. Hypomethylated ERV LTRs can be bound by transcription factors (TF) and serve as alternative promoters to induce the expression of oncogenes contributing to oncogenesis (top). They may also be decorated with H3K27ac and H3K4me1 (light green) and act as enhancers to drive the expression of adjacent or distal genes (bottom). Note: empty white circles represent unmethylated CpG dinucleotides. b HERV proteins, such as Env, can be expressed from intact HERV provirus ORFs in cancer cells (left). In breast and endometrial carcinoma models, Env has been detected on the cell membrane and is able to mediate cellular fusion with endothelial cells [154, 155] (middle). Env can promote tumorigenesis, for example by stimulating the RAS/RAF/MEK/ERK pathway in breast cancer models [156]. c Proposed model for therapeutic targeting of ERV-induced viral mimicry to promote immune detection of tumor cells. ERV reactivation can be induced by a number of therapeutic agents that target chromatin modifying enzymes (blue box). Derepression of ERV LTRs results in the production of dsRNA molecules, which can be detected by cytosolic dsRNA sensors TLR3 and MDA5 [101, 102, 134]. MDA5 binds to MAVS in the mitochondria and stimulates a signalling cascade which promotes the phosphorylation, dimerisation, and nuclear translocation of interferon regulatory factors (IRFs). IRFs drive a type I/III interferon response to spur cytokine production and increase the immunogenicity of the cell. Viral mimicry synergises with production and presentation of ERV-derived tumor associated antigens (green dot) via MHC-I, to increase the visibility of tumor cells for immunogenic death by cytolytic T cell activation