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

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  • Sunil Kumar Saini
  • Anne Mette Bjerregaard
  • Ashwin Unnikrishnan
  • Staffan Holmberg-Thydén
  • Annie Borch
  • Kathrine Valentini Jensen
  • Govardhan Anande
  • Amalie Kai Bentzen
  • Andrea Marion Marquard
  • Tripti Tamhane
  • Marianne Bach Treppendahl
  • Inge Høgh Dufva
  • Zoltan Szallasi
  • Nicola Ternette
  • Anders Gorm Pedersen
  • Aron Charles Eklund
  • John Pimanda
  • Sine Reker Hadrup

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.

Original languageEnglish
Article number5660
JournalNature Communications
Issue number1
Publication statusPublished - 2020

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