DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts
- PMID: 37872136
- PMCID: PMC10593957
- DOI: 10.1038/s41467-023-42417-w
DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts
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.
© 2023. Springer Nature Limited.
Conflict of interest statement
The University Hospital Tübingen and German Cancer Research Center (DKFZ, Heidelberg) is in the process of applying for a patent application (Patent number: EP23170469.3, Title: Neoepitope immunogenic peptides for cancer treatment and diagnosis) covering t-neopeptides that lists A.G., J.B., J.H., J.S.W, and C.P. as inventors. The other authors declare no competing interests.
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References
-
- Sahin U, et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature. 2017;547:222–226. - PubMed
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