Human endogenous retroviruses form a reservoir of T cell targets in hematological cancers

Sunil Kumar Saini ,Tripti Tamhane ,Staffan Holmberg-Thydén ,Marianne Bach Treppendahl ,Anne Ortved Gang ,Nicola Ternette ,Kathrine Valentini Jensen ,John E Pimanda ,Anne-Mette Bjerregaard ,Andrea Marion Marquard ,Govardhan Anande ,Zoltán Szállási ,Andreas Due Ørskov ,Kirsten Grønbæk ,Inge Høgh Dufva ,Aron Charles Eklund ,Annie Borch ,Ashwin Unnikrishnan ,Amalie Kai Bentzen ,Anders Gorm Pedersen ,Sine Reker Hadrup

doi:10.1038/s41467-020-19464-8

Abstract

Human endogenous retroviruses (HERV) form a substantial part of the human genome, but mostly remain transcriptionally silent under strict epigenetic regulation, yet can potentially be reactivated by malignant transformation or epigenetic therapies. Here, we evaluate the potential for T cell recognition of HERV elements in myeloid malignancies by mapping transcribed HERV genes and generating a library of 1169 potential antigenic HERV-derived peptides predicted for presentation by 4 HLA class I molecules. Using DNA barcode-labeled MHC-I multimers, we find CD8+ T cell populations recognizing 29 HERV-derived peptides representing 18 different HERV loci, of which HERVH-5, HERVW-1, and HERVE-3 have more profound responses; such HERV-specific T cells are present in 17 of the 34 patients, but less frequently in healthy donors. Transcriptomic analyses reveal enhanced transcription of the HERVs in patients; meanwhile DNA-demethylating therapy causes a small and heterogeneous enhancement in HERV transcription without altering T cell recognition. Our study thus uncovers T cell recognition of HERVs in myeloid malignancies, thereby implicating HERVs as potential targets for immunotherapeutic therapies.

Highlights

Human endogenous retroviruses (HERV) form a substantial part of the human genome, but mostly remain transcriptionally silent under strict epigenetic regulation, yet can potentially be reactivated by malignant transformation or epigenetic therapies
At a gross level across all the HERVs evaluated for T cell recognition, we found a tendency toward transcript levels being higher for those HERVs recognized by T cells compared to those not recognized, indicating that higher HERV expression may lead to enhanced levels of HERV T cell recognition
In this study, we investigated the presence of T cells specific to HERV-derived peptides in the myeloid hematological malignancies myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML)

Summary

Introduction

Human endogenous retroviruses (HERV) form a substantial part of the human genome, but mostly remain transcriptionally silent under strict epigenetic regulation, yet can potentially be reactivated by malignant transformation or epigenetic therapies. Transcriptomic analyses reveal enhanced transcription of the HERVs in patients; DNA-demethylating therapy causes a small and heterogeneous enhancement in HERV transcription without altering T cell recognition. Our study uncovers T cell recognition of HERVs in myeloid malignancies, thereby implicating HERVs as potential targets for immunotherapeutic therapies. Previous work has shown that the loss of DNA methylation mediated by DNA-demethylating therapy (hypomethylating agents [HMAs]), leads to an upregulation of single- and doublestranded HERV transcripts in human cancer cell lines, revealing a functional role of DNA methylation in repressing HERV expression[16,17,18]. To take advantage of this biological phenomenon, and to further boost immune recognition of malignant cells, several trials have opened, combining HMAs and immune checkpoint inhibitors[25]

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