Journal Article

Mapping the HLA ligandome landscape of acute myeloid leukemia: a targeted approach toward peptide-based immunotherapy

Kowalewski, D J, Schmid-Horch, B, Rammensee, H-G, Stevanović, S, Handel, M, Salih, H R, Mirza, N, Stickel, J S, Walz, S, Kanz, L, Berlin, C, Schuster, H

2015

Overview

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-γ 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/31 / 631/250/580 / 631/67/1059/2325 / 692/308/575 / 692/699/1541/1990/283/1897 / 82/16 / 82/58 / 82/80 / Acute myeloid leukemia / Amino Acid Sequence / Antigen (tumor-associated) / Antigens / Cancer Research / Cancer Vaccines - administration & dosage / Cancer Vaccines - genetics / Cancer Vaccines - immunology / Case-Control Studies / CD4 antigen / CD4-Positive T-Lymphocytes - immunology / CD4-Positive T-Lymphocytes - metabolism / CD4-Positive T-Lymphocytes - pathology / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / CD8-Positive T-Lymphocytes - pathology / Cell recognition / Chromosome mapping / Critical Care Medicine / Enzyme-linked immunosorbent assay / Epitope mapping / Epitopes, T-Lymphocyte - chemistry / Epitopes, T-Lymphocyte - genetics / Epitopes, T-Lymphocyte - immunology / Gene Expression / Genetic aspects / Health aspects / Hematology / Histocompatibility antigen HLA / Histocompatibility antigens / Histocompatibility Antigens Class I - chemistry / Histocompatibility Antigens Class I - genetics / Histocompatibility Antigens Class I - immunology / Histocompatibility Antigens Class II - chemistry / Histocompatibility Antigens Class II - genetics / Histocompatibility Antigens Class II - immunology / HLA histocompatibility antigens / Humans / Immunoprecipitation / Immunotherapy / Immunotherapy, Active - methods / Innovations / Intensive / Interferon / Internal Medicine / Leukemia / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - immunology / Leukemia, Myeloid, Acute - pathology / Leukemia, Myeloid, Acute - therapy / Leukocytes / Ligands / Lymphocytes T / Mass Spectrometry / Mass spectroscopy / Medicine / Medicine & Public Health / Methods / Molecular Sequence Data / Myeloid leukemia / Neoplasm Proteins - genetics / Neoplasm Proteins - immunology / Oncology / original-article / Patient outcomes / Peptide Mapping / Peptides / Peptides - chemistry / Peptides - genetics / Peptides - immunology / Target recognition / Tumors / Vaccines / γ-Interferon