Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry

Michal Bassani-Sternberg; Eva Bräunlein; Richard Klar; Thomas Engleitner; Pavel Sinitcyn; Stefan Audehm; Melanie Straub; Julia Weber; Julia Slotta-Huspenina; Katja Specht; Marc E Martignoni; Angelika Werner; Rüdiger Hein; Dirk H Busch; Christian Peschel; Roland Rad; Jürgen Cox; Matthias Mann; Angela M Krackhardt

doi:10.1038/ncomms13404

Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry

Michal Bassani-Sternberg, Eva Bräunlein, Richard Klar, Thomas Engleitner, Pavel Sinitcyn, Stefan Audehm, Melanie Straub, Julia Weber, Julia Slotta-Huspenina, Katja Specht, Marc E Martignoni, Angelika Werner, Rüdiger Hein, Dirk H Busch, Christian Peschel, Roland Rad, Jürgen Cox, Matthias Mann, Angela M Krackhardt

280 Citations (Scopus)

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.

Original language	English
Journal	Nature Communications
Volume	7
Pages (from-to)	13404
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms13404
Publication status	Published - 21 Nov 2016
Externally published	Yes

Keywords

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Bassani-Sternberg, M., Bräunlein, E., Klar, R., Engleitner, T., Sinitcyn, P., Audehm, S., Straub, M., Weber, J., Slotta-Huspenina, J., Specht, K., Martignoni, M. E., Werner, A., Hein, R., H Busch, D., Peschel, C., Rad, R., Cox, J., Mann, M., & Krackhardt, A. M. (2016). Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry. Nature Communications, 7, 13404. https://doi.org/10.1038/ncomms13404

Bassani-Sternberg, M, Bräunlein, E, Klar, R, Engleitner, T, Sinitcyn, P, Audehm, S, Straub, M, Weber, J, Slotta-Huspenina, J, Specht, K, Martignoni, ME, Werner, A, Hein, R, H Busch, D, Peschel, C, Rad, R, Cox, J, Mann, M & Krackhardt, AM 2016, 'Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry', Nature Communications, vol. 7, pp. 13404. https://doi.org/10.1038/ncomms13404

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title = "Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry",

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.",

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AU - Bassani-Sternberg, Michal

AU - Bräunlein, Eva

AU - Klar, Richard

AU - Engleitner, Thomas

AU - Sinitcyn, Pavel

AU - Audehm, Stefan

AU - Straub, Melanie

AU - Weber, Julia

AU - Slotta-Huspenina, Julia

AU - Specht, Katja

AU - Martignoni, Marc E

AU - Werner, Angelika

AU - Hein, Rüdiger

AU - H Busch, Dirk

AU - Peschel, Christian

AU - Rad, Roland

AU - Cox, Jürgen

AU - Mann, Matthias

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N2 - 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.

AB - 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.

KW - Journal Article

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SN - 2041-1723

VL - 7

SP - 13404

JO - Nature Communications

JF - Nature Communications

ER -

Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry

Abstract

Keywords

UN SDGs

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