Abstract
Although mutations may represent attractive targets for immunotherapy, direct identification of mutated peptide ligands isolated from human leucocyte antigens (HLA) on the surface of native tumour tissue has so far not been successful. Using advanced mass spectrometry (MS) analysis, we survey the melanoma-associated immunopeptidome to a depth of 95,500 patient-presented peptides. We thereby discover a large spectrum of attractive target antigen candidates including cancer testis antigens and phosphopeptides. Most importantly, we identify peptide ligands presented on native tumour tissue samples harbouring somatic mutations. Four of eleven mutated ligands prove to be immunogenic by neoantigen-specific T-cell responses. Moreover, tumour-reactive T cells with specificity for selected neoantigens identified by MS are detected in the patient's tumour and peripheral blood. We conclude that direct identification of mutated peptide ligands from primary tumour material by MS is possible and yields true neoepitopes with high relevance for immunotherapeutic strategies in cancer.
Highlights
Mutations may represent attractive targets for immunotherapy, direct identification of mutated peptide ligands isolated from human leucocyte antigens (HLA) on the surface of native tumour tissue has so far not been successful
We demonstrate this by showing significant positive correlation between the number of identified peptides in HLA class I peptidome and the amount of recovered beta-2 microglobulin (B2M) in each tissue (Supplementary Fig. 1a and b)
We hereby present for the first time integrative classes I and II immunopeptidomes of native melanoma tissue samples resulting in the identification of almost 100,000 peptide ligands naturally presented on the tumour
Summary
Mutations may represent attractive targets for immunotherapy, direct identification of mutated peptide ligands isolated from human leucocyte antigens (HLA) on the surface of native tumour tissue has so far not been successful. A number of tumour-associated antigens (TAA) have been evaluated as target antigens in clinical investigations especially in patients with melanoma These include antigens derived from differentiation antigens and cancer testis antigens[3,4]. Mutated peptide ligands identified by MS were derived from analyses of monoclonal cell lines only[21,22,23], not representing the complex heterogeneity of native tumours Thereby, especially those clonal mutations representing particular promising target antigens for prolonged tumour rejection[24] may be missed. We discover tumour-specific neoantigens in selected patients validated by the proof of potent patients’ derived neoantigen-specific anti-tumour immune responses These data demonstrate that high sensitivity MS is a powerful tool to identify neoantigens highly relevant for the development and optimization of personalized immunotherapies in patients with cancer
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