DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts
(1) Goyal A (2) Bauer J (3) Hey J (4) Papageorgiou DN (5) Stepanova E (6) Daskalakis M (7) Scheid J (8) Dubbelaar M (9) Klimovich B (10) Schwarz D (11) Mrklin M (12) Roerden M (13) Lin YY (14) Ma T (15) Mcke O (16) Rammensee HG (17) Lbbert M (18) Loayza-Puch F (19) Krijgsveld J (20) Walz JS (21) Plass C
(1) Goyal A (2) Bauer J (3) Hey J (4) Papageorgiou DN (5) Stepanova E (6) Daskalakis M (7) Scheid J (8) Dubbelaar M (9) Klimovich B (10) Schwarz D (11) Mrklin M (12) Roerden M (13) Lin YY (14) Ma T (15) Mcke O (16) Rammensee HG (17) Lbbert M (18) Loayza-Puch F (19) Krijgsveld J (20) Walz JS (21) Plass C
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.
Author Info:
(1) Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany. (2) Department of Peptide-based Immunotherapy, University of Tbingen and University Hospital Tb
ingen, Tbingen, Germany. Institute for Cell Biology, Department of Immunology, University of Tbingen, Tbingen, Germany. Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tbingen, Tbingen, Germany. (3) Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany. German-Israeli Helmholtz Research School in Cancer Biology, Heidelberg, Germany. German Center for Lung Research, (DZL) partner site Heidelberg, Heidelberg, Germany. (4) Division of Proteomics of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. Heidelberg University, Medical Faculty, Heidelberg, Germany. (5) Translational Control and Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany. (6) Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Hematology and Central Hematology Laboratory, Inselspital, Bern, University Hospital, University of Bern, Bern, Switzerland. (7) Department of Peptide-based Immunotherapy, University of Tbingen and University Hospital Tbingen, Tbingen, Germany. Institute for Cell Biology, Department of Immunology, University of Tbingen, Tbingen, Germany. Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tbingen, Tbingen, Germany. Quantitative Biology Center (QBiC), University of Tbingen, Tbingen, Germany. (8) Department of Peptide-based Immunotherapy, University of Tbingen and University Hospital Tbingen, Tbingen, Germany. Institute for Cell Biology, Department of Immunology, University of Tbingen, Tbingen, Germany. Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tbingen, Tbingen, Germany. Quantitative Biology Center (QBiC), University of Tbingen, Tbingen, Germany. (9) Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tbingen, Tbingen, Germany. Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tbingen, Tbingen, Germany. (10) Division of Proteomics of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. (11) Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tbingen, Tbingen, Germany. Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tbingen, Tbingen, Germany. (12) Department of Peptide-based Immunotherapy, University of Tbingen and University Hospital Tbingen, Tbingen, Germany. Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tbingen, Tbingen, Germany. (13) Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany. (14) Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. (15) Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany. (16) Institute for Cell Biology, Department of Immunology, University of Tbingen, Tbingen, Germany. Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tbingen, Tbingen, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany. (17) Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. (18) Translational Control and Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany. (19) Division of Proteomics of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. Heidelberg University, Medical Faculty, Heidelberg, Germany. (20) Department of Peptide-based Immunotherapy, University of Tbingen and University Hospital Tbingen, Tbingen, Germany. juliane.walz@med.uni-tuebingen.de. Institute for Cell Biology, Department of Immunology, University of Tbingen, Tbingen, Germany. juliane.walz@med.uni-tuebingen.de. Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tbingen, Tbingen, Germany. juliane.walz@med.uni-tuebingen.de. Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tbingen, Tbingen, Germany. juliane.walz@med.uni-tuebingen.de. (21) Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany. c.plass@dkfz.de. German Center for Lung Research, (DZL) partner site Heidelberg, Heidelberg, Germany. c.plass@dkfz.de. German Cancer Consortium (DKTK), Heidelberg, Germany. c.plass@dkfz.de.
Citation: Nat Commun 2023 Oct 23 14:6731 Epub10/23/2023
