Identification of a shared HLA-A*0201-restricted T-cell epitope from the melanoma antigen tyrosinase-related protein 2 (TRP2).
Identification of a shared HLA-A*0201-restricted T-cell epitope from the melanoma antigen tyrosinase-related protein 2 (TRP2).
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发表时间：
1998-11
期刊：
影响因子：
11.2
通讯作者：
M. Parkhurst;E. Fitzgerald;S. Southwood;Alessandro Sette;Steven A. Rosenberg;Yutaka Kawakami
中科院分区：
文献类型：
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作者：
M. Parkhurst;E. Fitzgerald;S. Southwood;Alessandro Sette;Steven A. Rosenberg;Yutaka Kawakami
酪氨酸酶相关蛋白2（TRP 2）是一种黑素酶，在大多数哺乳动物黑素细胞和黑色素瘤中表达。该蛋白质已被鉴定为在HLA-A31和HLA-A33的背景下由源自肿瘤浸润淋巴细胞的肿瘤反应性CTL识别的黑素瘤抗原。与HLA-A*0201（约46%）相比，美国黑色素瘤患者中这些HLA-A等位基因的频率较低（HLA-A31约6%，HLA-A33约2%）。因此，为了显着扩大基于TRP 2的免疫疗法在治疗黑色素瘤患者中的应用，我们通过筛选TRP 2衍生肽来诱导黑色素瘤反应性CTL，从该蛋白质中寻找新的HLA-A*0201限制性表位。基于允许的HLA-A*0201结合基序从TRP 2中选择51个肽，并且具有最高实验确定的结合亲和力的21个肽用于体外刺激来自HLA-A*0201+黑素瘤患者的外周血淋巴细胞。一种肽TRP 2（180-188）（SVYDFFVWL）诱导了来自四名患者中的三名患者的CTL，这些患者特异性地识别肽脉冲的T2细胞、表达HLA-A*0201和TRP 2的COS-7细胞以及HLA-A2+ TRP 2+黑色素瘤。TRP 2（180-188）与先前鉴定的在H-2Kb背景下由鼠黑素瘤反应性CTL识别的TRP 2表位相同。这些结果表明，TRP 2可能是有用的小鼠肿瘤免疫治疗模型的发展和治疗的黑色素瘤患者的HLA表达的多样性。
Tyrosinase-related protein 2 (TRP2) is a melanosomal enzyme expressed in most mammalian melanocytes and melanomas. This protein has been identified as a melanoma antigen recognized by tumor reactive CTLs derived from tumor infiltrating lymphocytes in the context of HLA-A31 and HLA-A33. The frequencies of these HLA-A alleles among melanoma patients in the United States is low (approximately 6% for HLA-A31 and approximately 2% for HLA-A33) compared with that of HLA-A*0201 (approximately 46%). Therefore, to extend significantly the use of TRP2-based immunotherapies for the treatment of patients with melanoma, we searched for new HLA-A*0201-restricted epitopes from this protein by screening TRP2-derived peptides for the induction of melanoma-reactive CTL. Fifty-one peptides were selected from TRP2 based on a permissive HLA-A*0201 binding motif, and the 21 peptides with the highest experimentally determined binding affinities were used to stimulate peripheral blood lymphocytes from HLA-A*0201+ melanoma patients in vitro. One peptide, TRP2(180-188) (SVYDFFVWL), induced CTLs from three of four patients that specifically recognized peptide-pulsed T2 cells, COS-7 cells expressing HLA-A*0201 and TRP2, and HLA-A2+ TRP2+ melanomas. TRP2(180-188) is identical to a previously identified TRP2 epitope recognized by murine melanoma-reactive CTLs in the context of H-2Kb. These results suggest that TRP2 may be useful for the development of murine tumor immunotherapy models and for the treatment of melanoma patients who are diverse in HLA expression.