Human endogenous retroviruses form a reservoir of T cell targets in hematological cancers.
Sunil Kumar SainiAndreas Due ØrskovAnne-Mette BjerregaardAshwin UnnikrishnanStaffan Holmberg-ThydenAnnie BorchKathrine Valentini JensenGovardhan AnandeAmalie Kai BentzenAndrea Marion MarquardTripti TamhaneMarianne Bach TreppendahlAnne Ortved GangInge Høgh DufvaZoltan SzallasiNicola TernetteAnders Gorm PedersenAron Charles EklundJohn E PimandaKirsten GrønbækSine Reker HadrupPublished in: Nature communications (2020)
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.
Keyphrases
- endothelial cells
- end stage renal disease
- genome wide
- ejection fraction
- newly diagnosed
- peritoneal dialysis
- prognostic factors
- bone marrow
- acute myeloid leukemia
- induced pluripotent stem cells
- pluripotent stem cells
- dendritic cells
- transcription factor
- patient reported outcomes
- single cell
- high resolution
- single molecule
- human health
- mesenchymal stem cells
- risk assessment
- autism spectrum disorder
- mass spectrometry
- genetic diversity
- childhood cancer