Bilich and Nelde et al. performed mass spectrometry-based HLA ligandome analysis of PBMCs from primary chronic myeloid leukemia (CML) in comparison to normal hematological tissues or CML patients in deep molecular remission to reveal a panel of novel, non-mutated, CML-associated target epitopes. Limited pre-existing epitope-specific T cells were observed in CML patients, but in vitro priming resulted in multifunctional, cytotoxic, peptide-specific CD8+ T cells for most tested epitopes in both healthy volunteer and CML patient samples. Viral epitope-specific CD8+ T cells in patients being treated with TKIs showed reduced functionality.
Anti-leukemia 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 to strengthen 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 specimen and samples of CML patients in deep molecular remission delineated a panel of novel, frequently presented, CML-exclusive peptides. These non-mutated target antigens are of particular relevance since our extensive data mining approach suggests absence of naturally presented, BCR-ABL- and ABL-BCR-derived, HLA-restricted peptides and 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 of healthy volunteers and CML patients. These antigens are thus prime candidates for T cell-based immunotherapeutic approaches that may prolong TKI-free survival and even mediate cure of CML patients.