Advertisement

The HLA ligandome landscape of chronic myeloid leukemia delineates novel T-cell epitopes for immunotherapy

Tatjana Bilich, Annika Nelde, Leon Bichmann, Malte Roerden, Helmut R. Salih, Daniel J. Kowalewski, Heiko Schuster, Chih-Chiang Tsou, Ana Marcu, Marian C. Neidert, Maren Lübke, Jonas Rieth, Mirle Schemionek, Tim H. Brümmendorf, Vladan Vucinic, Dietger Niederwieser, Jens Bauer, Melanie Märklin, Janet K. Peper, Reinhild Klein, Oliver Kohlbacher, Lothar Kanz, Hans-Georg Rammensee, Stefan Stevanović and Juliane S. Walz

Key Points

  • Mass spectrometry–based HLA ligandome analysis of primary CML patient samples revealed a panel of novel CML-associated target antigens.

  • These antigens induced multifunctional T-cell responses and may be used as targets for T-cell–based immunotherapeutic approaches.

Abstract

Antileukemia immunity plays an important role in disease control and maintenance of tyrosine kinase inhibitor (TKI)-free remission in chronic myeloid leukemia (CML). Thus, antigen-specific immunotherapy holds promise for strengthening immune control in CML but requires the identification of CML-associated targets. In this study, we used a mass spectrometry–based approach to identify naturally presented HLA class I– and class II–restricted peptides in primary CML samples. Comparative HLA ligandome profiling using a comprehensive dataset of different hematological benign specimens and samples from CML patients in deep molecular remission delineated a panel of novel frequently presented CML-exclusive peptides. These nonmutated target antigens are of particular relevance because our extensive data-mining approach suggests the absence of naturally presented BCR-ABL– and ABL-BCR–derived HLA-restricted peptides and the lack of frequent tumor-exclusive presentation of known cancer/testis and leukemia-associated antigens. Functional characterization revealed spontaneous T-cell responses against the newly identified CML-associated peptides in CML patient samples and their ability to induce multifunctional and cytotoxic antigen-specific T cells de novo in samples from healthy volunteers and CML patients. Thus, these antigens are prime candidates for T-cell–based immunotherapeutic approaches that may prolong TKI-free survival and even mediate cure of CML patients.

  • Submitted July 31, 2018.
  • Accepted December 1, 2018.
View Full Text