Identification of HLA-A2-or HLA-A24-restricted CTL epitopes possibly useful for glypican-3-specific immunotherapy of hepatocellular carcinoma
Identification of HLA-A2-or HLA-A24-restricted CTL epitopes possibly useful for glypican-3-specific immunotherapy of hepatocellular carcinoma
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DOI：
10.1158/1078-0432.ccr-05-2267
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发表时间：
2006-05-01
影响因子：
11.5
通讯作者：
Nishimura, Y
中科院分区：
文献类型：
--
作者：
Komori, H;Nakatsura, T;Nishimura, Y
目的和实验设计：我们以前报道过磷脂酰肌醇蛋白聚糖-3（GPC 3）的过表达，特别是在肝细胞癌（HCC）和黑色素瘤在人类，它是有用的作为一种新的肿瘤标志物。我们还报告说，用H-2K（d）限制性小鼠GPC 3（298-306）（EYILSLEEL）肽脉冲的树突状细胞预免疫BALB/c小鼠，可以阻止表达肿瘤的小鼠GPC 3的生长。由于H-2K（d）和HLA-A24（A*2402）之间肽结合基序的相似性，因此GPC 3（298-306）肽似乎可用于患有HCC和黑素瘤的HLA-A24（+）患者的免疫治疗。在本报告中，我们研究了GPC 3298 -306肽是否可以从HLA-A24（A*2402）（+）HCC患者的外周血单个核细胞（PBMC）中诱导GPC 3反应性CTL。结果：GPC 3（144-152）（FVGSTDV）肽段能诱导HLA-A2. 1（HHD）转基因小鼠产生肽反应性CTL，但不诱导自身免疫。在8名HLA-A2（+）GPC 3（+）HCC患者中的5名中，通过用肽体外刺激从PBMC产生GPC 3（144-152）肽反应性CTL，并且在6名HLA-A24（+）GPC 3（+）HCC患者中的4名中也从PBMC产生GPC 3（298-306）肽反应性CTL。这些CTL的接种减少了植入到非肥胖糖尿病/严重的联合免疫缺陷小鼠的人肝癌肿瘤质量。结论：我们的研究提出了这种可能性，这些GPC 3肽，因此可能适用于癌症免疫治疗的大量肝癌患者。
Purpose and Experimental Design: We previously reported that glypican-3 (GPC3) was overexpressed, specifically in hepatocellular carcinoma (HCC) and melanoma in humans, and it was useful as a novel tumor marker. We also reported that the preimmunization of BALB/c mice with dendritic cells pulsed with the H-2K(d)-restricted mouse GPC3(298-306) (EYILSLEEL) peptide prevented the growth of tumor-expressing mouse GPC3. Because of similarities in the peptide binding motifs between H-2K(d) and HLA-A24 (A*2402), the GPC3(298-306) peptide therefore seemed to be useful for the immunotherapy of HLA-A24(+) patients with HCC and melanoma. In this report, we investigated whether the GPC3298-306 peptide could induce GPC3-reactive CTLs from the peripheral blood mononuclear cells (PBMC) of HLA-A24 (A*2402)(+) HCC patients. In addition, we used HLA-A2.1 (HHD) transgenic mice to identify the HLA-A2 (A*0201)- restricted GPC3 epitopes to expand the applications of GPC3-based immunotherapy to the HLA-A2(+) HCC patients.Results: We found that the GPC3(144-152) (FVGEFFTDV) peptide could induce peptide-reactive CTLs in HLA-A2.1 (HHD) transgenic mice without inducing autoimmunity. In five out of eight HLA-A2(+) GPC3(+) HCC patients, the GPC3(144-152) peptide-reactive CTLs were generated from PBMCs by in vitro stimulation with the peptide and the GPC3(298-306) peptide-reactive CTLs were also generated from PBMCs in four of six HLA-A24(+) GPC3(+) HCC patients. The inoculation of these CTLs reduced the human HCC tumor mass implanted into nonobese diabetic/ severe combined immunodeficiency mice.Conclusion: Our study raises the possibility that these GPC3 peptides may therefore be applicable to cancer immunotherapy for a large number of HCC patients.