1. DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts.
- Author
-
Goyal, Ashish, Bauer, Jens, Hey, Joschka, Papageorgiou, Dimitris N., Stepanova, Ekaterina, Daskalakis, Michael, Scheid, Jonas, Dubbelaar, Marissa, Klimovich, Boris, Schwarz, Dominic, Märklin, Melanie, Roerden, Malte, Lin, Yu-Yu, Ma, Tobias, Mücke, Oliver, Rammensee, Hans-Georg, Lübbert, Michael, Loayza-Puch, Fabricio, Krijgsveld, Jeroen, and Walz, Juliane S.
- Subjects
HLA histocompatibility antigens ,HISTONE deacetylase inhibitors ,T cells ,CANCER cells - Abstract
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. Epigenetic therapies are known to synergize with immunotherapies through the de-repression of endogenous retroviral element (ERV)-encoded promoters. Here the authors identify treatment-induced neoantigens and validate their ability to induce T cell response and anti-tumor effects in vitro and in patient samples. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF