Proteasome inhibitors induce the presentation of an Epstein-Barr virus nuclear antigen 1-derived cytotoxic T lymphocyte epitope in Burkitt's lymphoma cells
Proteasome inhibitors induce the presentation of an Epstein-Barr virus nuclear antigen 1-derived cytotoxic T lymphocyte epitope in Burkitt's lymphoma cells
复制标题
DOI：
10.1111/j.1365-2567.2011.03416.x
复制
发表时间：
2011-05-01
期刊：
影响因子：
6.4
通讯作者：
Gavioli, Riccardo
中科院分区：
文献类型：
--
作者：
Destro, Federica;Sforza, Fabio;Gavioli, Riccardo
EB病毒（EBV）核抗原1（EBNA 1）通常在所有EBV相关肿瘤中表达，因此是免疫治疗的一个有趣靶点。然而，识别和消除EBV转化和伯基特淋巴瘤（BL）细胞的细胞毒性T淋巴细胞（CTL）特异性内源性EBNA 1衍生表位的证据仍然难以捉摸。我们在此证实，对HLA-B35/B53呈递的EBNA 1衍生的HPVGEADYFEY（HPV）表位特异的CTL在大多数HLA-B35个体中是可检测的，并且识别EBV转化的B淋巴细胞，从而证明GAr结构域不完全抑制HPV表位的I类呈递。相反，BL细胞不被HPV特异性CTL识别，这表明其他机制有助于提供对EBNA 1特异性CTL介导的裂解的完全保护。BL细胞和淋巴质体细胞系（LCL）之间的主要差异之一是蛋白酶体;事实上，BL细胞的蛋白酶体显示出远低于LCL的蛋白酶体的胰凝乳蛋白酶和胰蛋白酶样活性。因此，低效的蛋白酶体加工可能是该表位在BL细胞中呈现不佳的主要原因。有趣的是，我们发现用蛋白酶体抑制剂治疗部分恢复了BL细胞呈递HPV表位的能力。这表明来自BL细胞的蛋白酶体虽然在降解参比底物方面不如来自LCL的蛋白酶体有效，但能够破坏HPV表位，然而，其可以在蛋白酶体的部分抑制后产生和呈递。这些发现表明，单独或与其他药物联合使用蛋白酶体抑制剂，作为治疗携带EBNA 1的肿瘤的策略。
P>The Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is generally expressed in all EBV-associated tumours and is therefore an interesting target for immunotherapy. However, evidence for the recognition and elimination of EBV-transformed and Burkitt's lymphoma (BL) cells by cytotoxic T lymphocytes (CTLs) specific for endogenously presented EBNA1-derived epitopes remains elusive. We confirm here that CTLs specific for the HLA-B35/B53-presented EBNA1-derived HPVGEADYFEY (HPV) epitope are detectable in the majority of HLA-B35 individuals, and recognize EBV-transformed B lymphocytes, thereby demonstrating that the GAr domain does not fully inhibit the class I presentation of the HPV epitope. In contrast, BL cells are not recognized by HPV-specific CTLs, suggesting that other mechanisms contribute to providing a full protection from EBNA1-specific CTL-mediated lysis. One of the major differences between BL cells and lymphoplastoid cell lines (LCLs) is the proteasome; indeed, proteasomes from BL cells demonstrate far lower chymotryptic and tryptic-like activities compared with proteasomes from LCLs. Hence, inefficient proteasomal processing is likely to be the main reason for the poor presentation of this epitope in BL cells. Interestingly, we show that treatments with proteasome inhibitors partially restore the capacity of BL cells to present the HPV epitope. This indicates that proteasomes from BL cells, although less efficient in degrading reference substrates than proteasomes from LCLs, are able to destroy the HPV epitope, which can, however, be generated and presented after partial inhibition of the proteasome. These findings suggest the use of proteasome inhibitors, alone or in combination with other drugs, as a strategy for the treatment of EBNA1-carrying tumours.