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

Sunil Kumar Saini, Andreas Due Ørskov, 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, Anne Ortved Gang, Inge Høgh Dufva, Zoltan Szallasi, Nicola Ternette, Anders Gorm Pedersen, Aron Charles Eklund, John Pimanda, Kirsten Grønbæk and Sine Reker Hadrup ()
Additional contact information
Sunil Kumar Saini: Technical University of Denmark
Andreas Due Ørskov: Rigshospitalet, Copenhagen University Hospital
Anne-Mette Bjerregaard: Technical University of Denmark
Ashwin Unnikrishnan: Lowy Cancer Research Centre, UNSW
Staffan Holmberg-Thydén: Technical University of Denmark
Annie Borch: Technical University of Denmark
Kathrine Valentini Jensen: Technical University of Denmark
Govardhan Anande: Lowy Cancer Research Centre, UNSW
Amalie Kai Bentzen: Technical University of Denmark
Andrea Marion Marquard: Technical University of Denmark
Tripti Tamhane: Technical University of Denmark
Marianne Bach Treppendahl: Rigshospitalet, Copenhagen University Hospital
Anne Ortved Gang: Herlev Hospital, Copenhagen University Hospital
Inge Høgh Dufva: Herlev Hospital, Copenhagen University Hospital
Zoltan Szallasi: Technical University of Denmark
Nicola Ternette: University of Oxford
Anders Gorm Pedersen: Technical University of Denmark
Aron Charles Eklund: Technical University of Denmark
John Pimanda: Lowy Cancer Research Centre, UNSW
Kirsten Grønbæk: Rigshospitalet, Copenhagen University Hospital
Sine Reker Hadrup: Technical University of Denmark

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19464-8

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