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Cited by 102Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesEpigenetics and DNA Methylation

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

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Goyal, Ashish, Bauer, Jens, Hey, Joschka, Papageorgiou, Dimitris N., Stepanova, Ekaterina, Daskalakis, Michael, Scheid, Jonas, Dubbelaar, Marissa +13 more·2023·Nature Communications
DOI 10.1038/s41467-023-42417-wPMC PMC10593957
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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.

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Authors
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.
Affiliations
  • German Cancer Research Center (DE)
  • Universitätsklinikum Tübingen (DE)
  • University of Bern (CH)
  • University of Freiburg (DE)
  • Deutsches Konsortium für Translationale Krebsforschung (DE)
Corresponding author
  • Walz, Juliane S.
  • Plass, Christoph
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-10-23
Volume
14
Issue
1
Pages
6731-6731
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-42417-w
PMC
PMC10593957
OpenAlex
W4387871908
Cited by
102
References
6
Citations by year
2026: 40 · 2025: 35 · 2024: 25 · 2023: 2
FWCI
12.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Bern Open Repository and Information System (University of Bern) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Open Access CRIS of the University of Bern
Funders
  • Deutsche Forschungsgemeinschaft (FOR2674 (A01), FOR2674 (A09), SFB1324, EXC2180‑390900677, CIBSS – EXC 2189 – Project ID 390939984, WA 4608/1-2, TRR167, CRC 1160, CRC 1453-Project ID 431984000/S1, SFB1479-Project ID 441891347/S1, SFB-1479 – Project ID: 441891347)
  • German-Israeli Helmholtz International Research School Cancer-TRAX (HIRS-0003).
  • Wilhelm Sander-Stiftung (2016.177.3)
  • José Carreras Leukämie-Stiftung (DJCLS 05 R/2017)
  • Deutsche Krebshilfe (70114948)
  • Bundesministerium für Bildung und Forschung (FKZ:01KI20130, FKZ 01ZZ1801B)
  • Zentren für Personalisierte Medizin (ZPM). Fortüne Program of the University of Tübingen
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
endogenous retroviruses, hypomethylating agents, histone deacetylase inhibitors, epigenetic therapy, T cell response, decitabine, acute myeloid leukemia, cancer immunotherapy
MeSH terms
Humans, Neoplasms, T-Lymphocytes, Histocompatibility Antigens Class I, Endogenous Retroviruses, Histone Deacetylase Inhibitors

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