학술논문
Human endogenous retroviruses form a reservoir of T cell targets in hematological cancers.
Document Type
Academic Journal
Author
Saini SK; Department of Health Technology, Section of Experimental and Translational Immunology, Technical University of Denmark, Kongens Lyngby, Denmark.; Ørskov AD; Department of Haematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.; Bjerregaard AM; Department of Health Technology, Section of Experimental and Translational Immunology, Technical University of Denmark, Kongens Lyngby, Denmark.; Unnikrishnan A; Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW, 2052, Australia.; Prince of Wales Clinical School, UNSW, Sydney, NSW, 2052, Australia.; Holmberg-Thydén S; Department of Health Technology, Section of Experimental and Translational Immunology, Technical University of Denmark, Kongens Lyngby, Denmark.; Department of Haematology, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.; Borch A; Department of Health Technology, Section of Experimental and Translational Immunology, Technical University of Denmark, Kongens Lyngby, Denmark.; Jensen KV; Department of Health Technology, Section of Experimental and Translational Immunology, Technical University of Denmark, Kongens Lyngby, Denmark.; Anande G; Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW, 2052, Australia.; Prince of Wales Clinical School, UNSW, Sydney, NSW, 2052, Australia.; Bentzen AK; Department of Health Technology, Section of Experimental and Translational Immunology, Technical University of Denmark, Kongens Lyngby, Denmark.; Marquard AM; Department of Health Technology, Section of Experimental and Translational Immunology, Technical University of Denmark, Kongens Lyngby, Denmark.; Tamhane T; Department of Health Technology, Section of Experimental and Translational Immunology, Technical University of Denmark, Kongens Lyngby, Denmark.; Treppendahl MB; Department of Haematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.; Gang AO; Department of Haematology, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.; Dufva IH; Department of Haematology, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.; Szallasi Z; Department of Health Technology, Section of Bioinformatics, Technical University of Denmark, Kongens Lyngby, Denmark.; Computational Health Informatics Program (CHIP), Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Ternette N; Nuffield Department of Medicine, University of Oxford, Oxford, UK.; Pedersen AG; Department of Health Technology, Section of Bioinformatics, Technical University of Denmark, Kongens Lyngby, Denmark.; Eklund AC; Department of Health Technology, Section of Bioinformatics, Technical University of Denmark, Kongens Lyngby, Denmark.; Pimanda J; Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW, 2052, Australia.; Prince of Wales Clinical School, UNSW, Sydney, NSW, 2052, Australia.; Haematology Department, South Eastern Area Laboratory Services, Prince of Wales Hospital, Randwick, NSW, 2031, Australia.; Grønbæk K; Department of Haematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.; Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, Copenhagen, Denmark.; Hadrup SR; Department of Health Technology, Section of Experimental and Translational Immunology, Technical University of Denmark, Kongens Lyngby, Denmark. sirha@dtu.dk.
Source
Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
Subject
Language
English
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.