TY - JOUR
T1 - Human endogenous retroviruses form a reservoir of T cell targets in hematological cancers
AU - Saini, Sunil Kumar
AU - Ørskov, Andreas Due
AU - Bjerregaard, Anne Mette
AU - Unnikrishnan, Ashwin
AU - Holmberg-Thydén, Staffan
AU - Borch, Annie
AU - Jensen, Kathrine Valentini
AU - Anande, Govardhan
AU - Bentzen, Amalie Kai
AU - Marquard, Andrea Marion
AU - Tamhane, Tripti
AU - Treppendahl, Marianne Bach
AU - Gang, Anne Ortved
AU - Dufva, Inge Høgh
AU - Szallasi, Zoltan
AU - Ternette, Nicola
AU - Pedersen, Anders Gorm
AU - Eklund, Aron Charles
AU - Pimanda, John
AU - Grønbæk, Kirsten
AU - Hadrup, Sine Reker
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-020-19464-8
DO - 10.1038/s41467-020-19464-8
M3 - Journal article
C2 - 33168830
AN - SCOPUS:85095706890
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5660
ER -
