Defining HLA-II Ligand Processing and Binding Rules with Mass Spectrometry Enhances Cancer Epitope Prediction.
Increasing evidence indicates CD4+ T cells can recognize cancer-specific antigens and control tumor growth. However, it remains difficult to predict the antigens that will be presented by human leukocyte antigen class II molecules (HLA-II), hindering efforts to optimally target them therapeutically. Obstacles include inaccurate peptide-binding prediction and unsolved complexities of the HLA-II pathway. To address these challenges, we developed an improved technology for discovering HLA-II binding motifs and conducted a comprehensive analysis of tumor ligandomes to learn processing rules relevant in the tumor microenvironment. We profiled >40 HLA-II alleles and showed that binding motifs were highly sensitive to HLA-DM, a peptide-loading chaperone. We also revealed that intratumoral HLA-II presentation was dominated by professional antigen-presenting cells (APCs) rather than cancer cells. Integrating these observations, we developed algorithms that accurately predicted APC ligandomes, including peptides from phagocytosed cancer cells. These tools and biological insights will enable improved HLA-II-directed cancer therapies.
['Abelin|Jennifer G|JG|', 'Harjanto|Dewi|D|', 'Malloy|Matthew|M|', 'Suri|Prerna|P|', 'Colson|Tyler|T|', 'Goulding|Scott P|SP|', 'Creech|Amanda L|AL|', 'Serrano|Lia R|LR|', 'Nasir|Gibran|G|', 'Nasrullah|Yusuf|Y|', 'McGann|Christopher D|CD|', 'Velez|Diana|D|', 'Ting|Ying S|YS|', 'Poran|Asaf|A|', 'Rothenberg|Daniel A|DA|', 'Chhangawala|Sagar|S|', 'Rubinsteyn|Alex|A|', 'Hammerbacher|Jeff|J|', 'Gaynor|Richard B|RB|', 'Fritsch|Edward F|EF|', 'Greshock|Joel|J|', 'Oslund|Rob C|RC|', 'Barthelme|Dominik|D|', 'Addona|Terri A|TA|', 'Arieta|Christina M|CM|', 'Rooney|Michael S|MS|']
D000465:Algorithms D000483:Alleles D017951:Antigen Presentation D000938:Antigen-Presenting Cells D000951:Antigens, Neoplasm D015496:CD4-Positive T-Lymphocytes D019496:Cancer Vaccines D066264:Datasets as Topic D018604:Epitope Mapping D006680:HLA Antigens D006681:HLA-D Antigens D000949:Histocompatibility Antigens Class II D006801:Humans D007167:Immunotherapy D013058:Mass Spectrometry D009369:Neoplasms D011485:Protein Binding D054730:Protein Interaction Domains and Motifs D012984:Software
HLA-II mass spectrometry cancer epitope prediction antigen HLA class II HLA ligandomics MHC RNA-Seq SILAC autophagy isotope labeling machine learning neoantigen peptide processing phagocytosis proteomics