Unmasking the suppressed immunopeptidome of EZH2-mutated diffuse large B-cell lymphomas through combination drug treatment Journal Article
| Authors: | Bourne, C. M.; Mun, S. S.; Dao, T.; Aretz, Z. E. H.; Molvi, Z.; Gejman, R. S.; Daman, A.; Takata, K.; Steidl, C.; Klatt, M. G.; Scheinberg, D. A. |
| Article Title: | Unmasking the suppressed immunopeptidome of EZH2-mutated diffuse large B-cell lymphomas through combination drug treatment |
| Abstract: | Exploring the repertoire of peptides presented on major histocompatibility complexes (MHCs) helps identify targets for immunotherapy in many hematologic malignancies. However, there is a paucity of such data for diffuse large B-cell lymphomas (DLBCLs), which might be explained by the profound downregulation of MHC expression in many DLBCLs, and in particular in the enhancer of zeste homolog 2 (EZH2)-mutated subgroup. Epigenetic drug treatment, especially in the context of interferon-g (IFN-g), restored MHC expression in DLBCL. In DLBCL, peptides presented on MHCs were identified via mass spectrometry after treatment with tazemetostat or decitabine alone or in combination with IFN-g. Such treatment synergistically increased the expression of MHC class I surface proteins up to 50-fold and the expression of class II surface proteins up to threefold. Peptides presented on MHCs increased to a similar extent for both class I and class II MHCs. Overall, these treatments restored the diversity of the immunopeptidome to levels described in healthy B cells for 2 of 3 cell lines and allowed the systematic search for new targets for immunotherapy. Consequently, we identified multiple MHC ligands from the regulator of G protein signaling 13 (RGS13) and E2F transcription factor 8 (E2F8) on different MHC alleles, none of which have been described in healthy tissues and therefore represent tumor-specific MHC ligands that are unmasked only after drug treatment. Overall, our results show that EZH2 inhibition in combination with decitabine and IFN-g can expand the repertoire of MHC ligands presented on DLBCLs by revealing suppressed epitopes, thus allowing the systematic analysis and identification of new potential immunotherapy targets. © 2022 by The American Society of Hematology. |
| Journal Title: | Blood Advances |
| Volume: | 6 |
| Issue: | 14 |
| ISSN: | 2473-9529 |
| Publisher: | American Society of Hematology |
| Date Published: | 2022-07-26 |
| Start Page: | 4107 |
| End Page: | 4121 |
| Language: | English |
| DOI: | 10.1182/bloodadvances.2021006069 |
| PUBMED: | 35561310 |
| PROVIDER: | scopus |
| PMCID: | PMC9327544 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 August 2022 -- Source: Scopus |
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