Science and Research

DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts

Immunotherapies targeting cancer-specific neoantigens have revolutionized the treatment of cancer patients. Recent evidence suggests that epigenetic therapies synergize with immunotherapies, mediated by the de-repression of endogenous retroviral element (ERV)-encoded promoters, and the initiation of transcription. Here, we use deep RNA sequencing from cancer cell lines treated with DNA methyltransferase inhibitor (DNMTi) and/or Histone deacetylase inhibitor (HDACi), to assemble a de novo transcriptome and identify several thousand ERV-derived, treatment-induced novel polyadenylated transcripts (TINPATs). Using immunopeptidomics, we demonstrate the human leukocyte antigen (HLA) presentation of 45 spectra-validated treatment-induced neopeptides (t-neopeptides) arising from TINPATs. We illustrate the potential of the identified t-neopeptides to elicit a T-cell response to effectively target cancer cells. We further verify the presence of t-neopeptides in AML patient samples after in vivo treatment with the DNMT inhibitor Decitabine. Our findings highlight the potential of ERV-derived neoantigens in epigenetic and immune therapies.

  • Goyal, A.
  • Bauer, J.
  • Hey, J.
  • Papageorgiou, D. N.
  • Stepanova, E.
  • Daskalakis, M.
  • Scheid, J.
  • Dubbelaar, M.
  • Klimovich, B.
  • Schwarz, D.
  • Märklin, M.
  • Roerden, M.
  • Lin, Y. Y.
  • Ma, T.
  • Mücke, O.
  • Rammensee, H. G.
  • Lübbert, M.
  • Loayza-Puch, F.
  • Krijgsveld, J.
  • Walz, J. S.
  • Plass, C.

Keywords

  • Humans
  • *Endogenous Retroviruses/genetics
  • Histone Deacetylase Inhibitors/pharmacology
  • *Neoplasms
  • T-Lymphocytes
  • Histocompatibility Antigens Class I
Publication details
DOI: 10.1038/s41467-023-42417-w
Journal: Nat Commun
Pages: 6731 
Number: 1
Work Type: Original
Location: TLRC
Disease Area: LC
Partner / Member: DKFZ
Access-Number: 37872136

DZL Engagements

chevron-down