Defining HLA-II Ligand Processing and Binding Rules with Mass Spectrometry Enhances Cancer Epitope Prediction
Defining HLA-II Ligand Processing and Binding Rules with Mass Spectrometry Enhances Cancer Epitope Prediction
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DOI：
10.1016/j.immuni.2019.08.012
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发表时间：
2019-10-15
期刊：
影响因子：
32.4
通讯作者：
Rooney, Michael S.
中科院分区：
文献类型：
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作者：
Abelin, Jennifer G.;Harjanto, Dewi;Rooney, Michael S.
越来越多的证据表明，CD 4（+）T细胞可以识别癌症特异性抗原并控制肿瘤生长。然而，仍然难以预测将由人类白细胞抗原II类分子（HLA-II）呈递的抗原，阻碍了在治疗上最佳靶向它们的努力。障碍包括不准确的肽结合预测和HLA-II途径的未解决的复杂性。为了应对这些挑战，我们开发了一种改进的技术来发现HLA-II结合基序，并对肿瘤配体进行了全面分析，以了解肿瘤微环境中相关的处理规则。我们分析了>40个HLA-II等位基因，并显示结合基序对HLA-DM（一种肽负载伴侣）高度敏感。我们还发现，肿瘤内HLA-II呈递主要由专职抗原呈递细胞（APC）而不是癌细胞。整合这些观察结果，我们开发了准确预测APC配体的算法，包括来自吞噬癌细胞的肽。这些工具和生物学见解将使改进的HLA-II导向的癌症疗法成为可能。
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.