Cytotoxic T cell targeting of TRP-2 sensitizes human malignant glioma to chemotherapy
Cytotoxic T cell targeting of TRP-2 sensitizes human malignant glioma to chemotherapy
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DOI：
10.1038/sj.onc.1208519
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发表时间：
2005-08-01
期刊：
影响因子：
8
通讯作者：
Yu, JS
中科院分区：
文献类型：
--
作者：
Liu, GT;Akasaki, Y;Yu, JS
酪氨酸酶相关蛋白（Tyrosinase-related protein，TRP）-2不仅在胶质瘤细胞上表达，而且由胶质瘤细胞表面MHC分子天然加工和提呈，并被TRP-2特异性细胞毒性T细胞识别。主动免疫治疗后，检测患者外周血单个核细胞（PBMC）中TRP-2特异性细胞毒性T淋巴细胞（CTL）活性。在两名对TRP-2表现出CTL应答的患者中，与疫苗接种前切除的自体细胞系相比，疫苗接种后切除的肿瘤细胞显示出显著较低的TRP-2表达和对卡铂和替莫唑胺较高的敏感性。两名患者中的一名在复发后接受了替莫唑胺治疗，并显着缓解。与野生型U-373（W-U373）相比，TRP-2转染的细胞系（TRP-2-U373）导致对卡铂和替莫唑胺的显著耐药性。TRP-2转染后，BCRP-1、MGMT、MDR-1、MRP-1和MRP-3等常见耐药相关蛋白的mRNA表达无明显变化。通过TRP-2特异性CTL系免疫选择TRP-2-U373肿瘤细胞。与TRP-2-U373相比，免疫选择的细胞（IS-TRP-2-U373）表现出对卡铂和替莫唑胺的显著增加的敏感性。我们首次提供了肿瘤相关抗原TRP-2的免疫靶向显著增加化疗敏感性的证据。
Tyrosinase-related protein (TRP)-2 is not only expressed on glioma cells, but is naturally processed and presented by their surface MHC molecules and is recognized by TRP-2-specific cytotoxic T cells. After active immunotherapy, we detected TRP-2-specific cytotoxic T lymphocyte (CTL) activity in patients' peripheral blood mononuclear cells (PBMC). Tumor cells from postvaccination resections showed significantly lower TRP-2 expression and higher sensitivity to carboplatin and temozolomide than those autologous cell lines from prevaccination resections in two patients who demonstrated CTL response to TRP-2. One of two patients underwent treatment with temozolomide after recurrence and responded dramatically. TRP-2-transfected cell line (TRP-2-U373) resulted in significant drug resistance to carboplatin and temozolomide compared to wild-type U-373 (W-U373). There was no significant difference, however, in the mRNA expression of other common drug resistance related proteins, such as BCRP-1, MGMT, MDR-1, MRP-1 and MRP-3, after TRP-2 transfection. TRP-2-U373 tumor cells were immunoselected by a TRP-2-specific CTL line. The immunoselected cells (IS-TRP-2-U373) demonstrated significantly increased sensitivity to carboplatin and temozolomide compared to TRP-2-U373. For the first time, we provide evidence that immunological targeting of tumor-associated antigen TRP-2 significantly increases sensitivity to chemotherapy.