2016,
Nature Communications.
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
Abstract:
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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#paper https://doi.org/10.1038/ncomms13404 Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry
这篇研究采用高灵敏度质谱技术，对25名黑色素瘤患者的原发肿瘤组织进行了全面的免疫肽谱学分析，发现了近10万个肿瘤相关肽段。研究团队还首次直接鉴定了携带突变的肽段，其中11个突变肽段在患者样本中得到证实。这些突变肽段中有4个显示出免疫原性，能够诱导患者体内T细胞产生针对癌症的免疫反应。这表明直接通过质谱技术识别突变肽段是寻找个性化肿瘤免疫治疗靶点的有效方法。此外，研究还在未富集的样本中检测到磷酸化肽段，为未来研发癌症免疫治疗提供了潜在目标。虽然该方法灵敏度仍需改进，但研究结果为癌症免疫治疗提供了重要的启示和新方向。