Abstract
Human endogenous retroviruses (hERVs) are remnants of exogenous retroviruses that have integrated into the genome throughout evolution. We developed a computational workflow, hervQuant, which identified more than 3,000 transcriptionally active hERVs within The Cancer Genome Atlas (TCGA) pan-cancer RNA-Seq database. hERV expression was associated with clinical prognosis in several tumor types, most significantly clear cell renal cell carcinoma (ccRCC). We explored two mechanisms by which hERV expression may influence the tumor immune microenvironment in ccRCC: (i) RIG-I-like signaling and (ii) retroviral antigen activation of adaptive immunity. We demonstrated the ability of hERV signatures associated with these immune mechanisms to predict patient survival in ccRCC, independent of clinical staging and molecular subtyping. We identified potential tumor-specific hERV epitopes with evidence of translational activity through the use of a ccRCC ribosome profiling (Ribo-Seq) dataset, validated their ability to bind HLA in vitro, and identified the presence of MHC tetramer-positive T cells against predicted epitopes. hERV sequences identified through this screening approach were significantly more highly expressed in ccRCC tumors responsive to treatment with programmed death receptor 1 (PD-1) inhibition. hervQuant provides insights into the role of hERVs within the tumor immune microenvironment, as well as evidence that hERV expression could serve as a biomarker for patient prognosis and response to immunotherapy.
Highlights
Human endogenous retroviruses are remnants of exogenous retroviruses integrated into the primate genome over evolutionary time [1]. hERVs share genomic similarities to other retroviruses, including the presence of functional and remnant 5′ and 3′ long terminal repeats (LTRs), and gag, pro, pol, and env genes
While several cancer types demonstrated similar hERV expression patterns based on tissue location (UCEC and UCS, HNSC and LUSC, KIRC and KIRP, and READ and COAD), the clustering observed between various tumor types suggests that hERV expression may be conserved among cancers across a variety of tissues
We report here a hierarchical analysis of hERV–immune microenvironment interactions within the The Cancer Genome Atlas (TCGA) pan-cancer dataset, integrated with Ribo-Seq data, RNA sequencing (RNA-Seq) data from immunotherapytreated patients, and functional biological assays, to provide insight into hERV immunobiology in cancer
Summary
Human endogenous retroviruses (hERVs) are remnants of exogenous retroviruses integrated into the primate genome over evolutionary time [1]. hERVs share genomic similarities to other retroviruses, including the presence of functional and remnant 5′ and 3′ long terminal repeats (LTRs), and gag, pro, pol, and env genes. A recent study by Rooney et al analyzed features associated with genes important for immune cytolytic activity, finding that one of these associated features was expression of a small subset of hERVs [15]. While this study provided evidence that hERV expression associated with an immune phenotype, the exploration of hERVs was limited by a small reference set, no reported mechanism of association or prognostic impact of hERV expression, and no confirmation of a hERV-specific immune population within any tumor type. Understanding patterns of hERV expression will allow for greater knowledge of the impact of hERVs on tumorimmune interactions, the design of new prognostic models based on hERV signatures, and further identification of tumor-specific hERV epitopes for targeted tumor vaccinations
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