PMID- 25092142 OWN - NLM STAT- MEDLINE DCOM- 20150508 LR - 20211203 IS - 1476-5551 (Electronic) IS - 0887-6924 (Linking) VI - 29 IP - 3 DP - 2015 Mar TI - Mapping the HLA ligandome landscape of acute myeloid leukemia: a targeted approach toward peptide-based immunotherapy. PG - 647-59 LID - 10.1038/leu.2014.233 [doi] AB - Identification of physiologically relevant peptide vaccine targets calls for the direct analysis of the entirety of naturally presented human leukocyte antigen (HLA) ligands, termed the HLA ligandome. In this study, we implemented this direct approach using immunoprecipitation and mass spectrometry to define acute myeloid leukemia (AML)-associated peptide vaccine targets. Mapping the HLA class I ligandomes of 15 AML patients and 35 healthy controls, more than 25 000 different naturally presented HLA ligands were identified. Target prioritization based on AML exclusivity and high presentation frequency in the AML cohort identified a panel of 132 LiTAAs (ligandome-derived tumor-associated antigens), and 341 corresponding HLA ligands (LiTAPs (ligandome-derived tumor-associated peptides)) represented subset independently in >20% of AML patients. Functional characterization of LiTAPs by interferon-gamma ELISPOT (Enzyme-Linked ImmunoSpot) and intracellular cytokine staining confirmed AML-specific CD8(+) T-cell recognition. Of note, our platform identified HLA ligands representing several established AML-associated antigens (e.g. NPM1, MAGED1, PRTN3, MPO, WT1), but found 80% of them to be also represented in healthy control samples. Mapping of HLA class II ligandomes provided additional CD4(+) T-cell epitopes and potentially synergistic embedded HLA ligands, allowing for complementation of a multipeptide vaccine for the immunotherapy of AML. FAU - Berlin, C AU - Berlin C AD - 1] Department of Immunology, Institute for Cell Biology, University of Tubingen, Tubingen, Germany [2] Department of Hematology and Oncology, University of Tubingen, Tubingen, Germany. FAU - Kowalewski, D J AU - Kowalewski DJ AD - Department of Immunology, Institute for Cell Biology, University of Tubingen, Tubingen, Germany. FAU - Schuster, H AU - Schuster H AD - Department of Immunology, Institute for Cell Biology, University of Tubingen, Tubingen, Germany. FAU - Mirza, N AU - Mirza N AD - 1] Department of Immunology, Institute for Cell Biology, University of Tubingen, Tubingen, Germany [2] Department of Hematology and Oncology, University of Tubingen, Tubingen, Germany. FAU - Walz, S AU - Walz S AD - 1] Department of Immunology, Institute for Cell Biology, University of Tubingen, Tubingen, Germany [2] Department of Hematology and Oncology, University of Tubingen, Tubingen, Germany. FAU - Handel, M AU - Handel M AD - Hospital Group South-West, Department of Orthopedics, Calw, Germany. FAU - Schmid-Horch, B AU - Schmid-Horch B AD - Institute for Clinical and Experimental Transfusion Medicine, University of Tubingen, Tubingen, Germany. FAU - Salih, H R AU - Salih HR AD - 1] Department of Hematology and Oncology, University of Tubingen, Tubingen, Germany [2] Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. FAU - Kanz, L AU - Kanz L AD - Department of Hematology and Oncology, University of Tubingen, Tubingen, Germany. FAU - Rammensee, H-G AU - Rammensee HG AD - 1] Department of Immunology, Institute for Cell Biology, University of Tubingen, Tubingen, Germany [2] Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. FAU - Stevanovic, S AU - Stevanovic S AD - 1] Department of Immunology, Institute for Cell Biology, University of Tubingen, Tubingen, Germany [2] Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. FAU - Stickel, J S AU - Stickel JS AD - 1] Department of Immunology, Institute for Cell Biology, University of Tubingen, Tubingen, Germany [2] Department of Hematology and Oncology, University of Tubingen, Tubingen, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140805 PL - England TA - Leukemia JT - Leukemia JID - 8704895 RN - 0 (Cancer Vaccines) RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Histocompatibility Antigens Class II) RN - 0 (Ligands) RN - 0 (NPM1 protein, human) RN - 0 (Neoplasm Proteins) RN - 0 (Peptides) RN - 117896-08-9 (Nucleophosmin) SB - IM EIN - Leukemia. 2016 Apr;30(4):1003-4. PMID: 27049048 MH - Amino Acid Sequence MH - CD4-Positive T-Lymphocytes/immunology/metabolism/pathology MH - CD8-Positive T-Lymphocytes/immunology/metabolism/pathology MH - Cancer Vaccines/administration & dosage/genetics/*immunology MH - Case-Control Studies MH - Epitopes, T-Lymphocyte/chemistry/genetics/immunology MH - Gene Expression MH - Histocompatibility Antigens Class I/chemistry/*genetics/immunology MH - Histocompatibility Antigens Class II/chemistry/*genetics/immunology MH - Humans MH - Immunoprecipitation MH - Immunotherapy, Active/*methods MH - Leukemia, Myeloid, Acute/genetics/immunology/pathology/*therapy MH - Ligands MH - Mass Spectrometry MH - Molecular Sequence Data MH - Neoplasm Proteins/genetics/*immunology MH - Nucleophosmin MH - Peptide Mapping MH - Peptides/chemistry/genetics/*immunology EDAT- 2014/08/06 06:00 MHDA- 2015/05/09 06:00 CRDT- 2014/08/06 06:00 PHST- 2014/04/23 00:00 [received] PHST- 2014/07/23 00:00 [revised] PHST- 2014/07/24 00:00 [accepted] PHST- 2014/08/06 06:00 [entrez] PHST- 2014/08/06 06:00 [pubmed] PHST- 2015/05/09 06:00 [medline] AID - leu2014233 [pii] AID - 10.1038/leu.2014.233 [doi] PST - ppublish SO - Leukemia. 2015 Mar;29(3):647-59. doi: 10.1038/leu.2014.233. Epub 2014 Aug 5.