文章：

卡非佐米改变骨髓瘤细胞的HLA呈递肽段谱，并损害具有芳香族C末端肽段的呈递

Carfilzomib alters the HLA-presented peptidome of myeloma cells and impairs presentation of peptides with aromatic C-termini

原文发布日期：2016-04-08

DOI: 10.1038/bcj.2016.14

类型: Original Article

开放获取: 是

英文摘要：

Recent studies suggest that multiple myeloma is an immunogenic disease, which might be effectively targeted by antigen-specific T-cell immunotherapy. As standard of care in myeloma includes proteasome inhibitor therapy, it is of great importance to characterize the effects of this treatment on HLA-restricted antigen presentation and implement only robustly presented targets for immunotherapeutic intervention. Here, we present a study that longitudinally and semi-quantitatively maps the effects of the proteasome inhibitor carfilzomib on HLA-restricted antigen presentation. The relative presentation levels of 4780 different HLA ligands were quantified in an in vitro model employing carfilzomib treatment of MM.1S and U266 myeloma cells, which revealed significant modulation of a substantial fraction of the HLA-presented peptidome. Strikingly, we detected selective down-modulation of HLA ligands with aromatic C-terminal anchor amino acids. This particularly manifested as a marked reduction in the presentation of HLA ligands through the HLA allotypes A*23:01 and A*24:02 on MM.1S cells. These findings implicate that carfilzomib mediates a direct, peptide motif-specific inhibitory effect on HLA ligand processing and presentation. As a substantial proportion of HLA allotypes present peptides with aromatic C-termini, our results may have broad implications for the implementation of antigen-specific treatment approaches in patients undergoing carfilzomib treatment.

摘要翻译： 

近期研究表明，多发性骨髓瘤是一种免疫原性疾病，或可通过抗原特异性T细胞免疫疗法进行靶向治疗。由于骨髓瘤的标准治疗方案包含蛋白酶体抑制剂疗法，明确该疗法对HLA限制性抗原呈递的影响并筛选具有稳定呈递特性的靶点用于免疫治疗干预至关重要。本文通过体外模型对蛋白酶体抑制剂卡非佐米作用于HLA限制性抗原呈递的效应进行了纵向半定量图谱分析：在经卡非佐米处理的MM.1S和U266骨髓瘤细胞中，对4780种不同HLA配体的相对呈递水平进行量化，结果显示大部分HLA呈递肽组发生显著调节。引人注目的是，我们观察到具有芳香族C末端锚定氨基酸的HLA配体出现选择性下调，这一现象在MM.1S细胞中通过HLA等位基因A*23:01和A*24:02呈递的HLA配体显著减少中尤为明显。这些发现提示卡非佐米对HLA配体的加工与呈递具有直接的肽基序特异性抑制作用。鉴于相当比例的HLA等位基因呈递的肽段均带有芳香族C末端，我们的研究结果可能对接受卡非佐米治疗患者实施抗原特异性治疗方案产生广泛影响。

原文链接：

Carfilzomib alters the HLA-presented peptidome of myeloma cells and impairs presentation of peptides with aromatic C-termini