1. Defining HLA-II Ligand Processing and Binding Rules with Mass Spectrometry Enhances Cancer Epitope Prediction.
- Author
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Abelin JG, Harjanto D, Malloy M, Suri P, Colson T, Goulding SP, Creech AL, Serrano LR, Nasir G, Nasrullah Y, McGann CD, Velez D, Ting YS, Poran A, Rothenberg DA, Chhangawala S, Rubinsteyn A, Hammerbacher J, Gaynor RB, Fritsch EF, Greshock J, Oslund RC, Barthelme D, Addona TA, Arieta CM, and Rooney MS
- Subjects
- Algorithms, Alleles, Antigen Presentation, Antigens, Neoplasm immunology, Antigens, Neoplasm metabolism, Datasets as Topic, HLA Antigens genetics, HLA-D Antigens metabolism, Humans, Neoplasms immunology, Protein Binding, Protein Interaction Domains and Motifs genetics, Software, Antigen-Presenting Cells immunology, CD4-Positive T-Lymphocytes immunology, Cancer Vaccines immunology, Epitope Mapping methods, HLA Antigens metabolism, Histocompatibility Antigens Class II genetics, Immunotherapy methods, Mass Spectrometry methods, Neoplasms therapy
- Abstract
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., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2019
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