Characterising a human endogenous retrovirus(HERV)-derived tumour-associated antigen: enriched RNA-Seq analysis of HERV-K(HML-2) in mantle cell lymphoma cell lines

Abstract

Background: The cell-surface attachment protein (Env) of the HERV-K(HML-2) lineage of endogenous retroviruses is a potentially attractive tumour-associated antigen for anti-cancer immunotherapy. The human genome contains around 100 integrated copies (called proviruses or loci) of the HERV-K(HML-2) virus and we argue that it is important for therapy development to know which and how many of these contribute to protein expression, and how this varies across tissues. We measured relative provirus expression in HERV-K(HML-2), using enriched RNA-Seq analysis with both short-and long-read sequencing, in three Mantle Cell Lymphoma cell lines (JVM2, Granta519 and REC1). We also confirmed expression of the Env protein in two of our cell lines using Western blotting, and analysed provirus expression data from all other relevant published studies. Results: Firstly, in both our and other reanalysed studies, approximately 10% of the transcripts mapping to HERV-K(HML-2) came from Env-encoding proviruses. Secondly, in one cell line the majority of the protein expression appears to come from one provirus (12q14.1). Thirdly, we find a strong tissue-specific pattern of provirus expression. Conclusions: A possible dependency of Env expression on a single provirus, combined with the earlier observation that this provirus is not present in all individuals and a general pattern of tissue-specific expression among proviruses, has serious implications for future HERV-K(HML-2)-targeted immunotherapy. Further research into HERV-K(HML-2) as a possible tumour-associated antigen in blood cancers requires a more targeted, proteome-based, screening protocol that will consider these polymorphisms within HERV-K(HML-2). We include a plan (and necessary alignments) for such work.

Human endogenous retroviruses in cancer: Expression, regulation and function (Review)

“…Nowadays, studies regarding HERVs are hampered due to a plethora of transcribed HERV RNAs in cancer and the lack of specific commercial antibodies ( 137 ). The emerging high-throughput RNA-sequencing technique may demonstrate a more explicit expression profile of HERVs and expand possible roles in cancer ( 137 , 138 ). Insufficient knowledge regarding HERV genes, their highly complex pattern of activation, and transcriptional and posttranscriptional regulation hinders the ability to study the mechanistic role of HERVs in numerous cancers.…”

Identification of Differentially Expressed Human Endogenous Retrovirus Families in Human Leukemia and Lymphoma Cell Lines and Stem Cells

“…Only reads that mapped uniquely to the virus metagenome were counted using the following settings: counted fragments (-p), only allow fragments with both reads aligned (-B), disabled multi-mapping. The multi-mapping option in featureCounts (-M) was not used because this might lead to overestimations ( 47 ). However, this is only relevant if the –a/-k option is used for mapping.…”

Human Endogenous Retrovirus K in Cancer: A Potential Biomarker and Immunotherapeutic Target

“…Additionally, the dependency of Env expression from a single provirus in a subset of individuals and a pattern of tissue-specific expression among proviruses in Mantle Cell lymphoma cell lines implies that HERV-K-targeted immunotherapy could be a precision medicine technique to specifically target the cell-specific aberrant transcription of this tumor-associated antigen in blood cancers. This could lead to a more targeted proteome-based screening protocol for HERV-K polymorphisms in blood cancers [ 15 ]. In short, all these studies show HERV-K expression as a target for cancer immunotherapy.…”

“…For example, env transcripts encoded by the HERV-K HML-2 subtype—hereafter abbreviated to HERV-K—the most studied HERV element, produce two oncogenic proteins (Rec and Np9) which are able to modulate cellular gene expression and induce cancer development [ 3 , 12 ]. Furthermore, its derived proteins could behave as tumor-associated neoantigens and induce immune responses in different types of cancer [ 3 , 4 , 12 , 14 , 15 , 16 ]. In this review, we describe the function of HERV-K in carcinogenesis, as well as its use as biomarkers and as targets for cancer immunotherapy.…”