WT1 as a Novel Target Antigen for Cancer Immunotherapy
WT1 as a Novel Target Antigen for Cancer Immunotherapy
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DOI：
10.2174/1568009023334088
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发表时间：
2002-01-01
影响因子：
3
通讯作者：
Sugiyama, H.
中科院分区：
文献类型：
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作者：
Oka, Y.;Tsuboi, A.;Sugiyama, H.
野生型Wilms肿瘤基因WT1不仅在大多数急性髓细胞性、急性淋巴细胞性和慢性髓细胞性白血病中高水平表达，而且在包括肺癌在内的各种类型的实体肿瘤中也有高水平表达。我们测试了该基因产物（WT1）在人体外系统和小鼠体内系统中作为肿瘤特异性免疫治疗靶抗原的能力。后者，我们可以在体内评价接种WT1疫苗的疗效和副作用。在人体外系统中，两个含有HLA-A2.1结合锚基序的WT1肽被确定与HLA-A2.1分子结合。在体外用这两种肽分别脉冲tap缺陷T2细胞反复刺激hla - a2.1阳性供者的外周血单个核细胞（PBMC），并诱导cd8阳性细胞毒性T淋巴细胞（ctl）特异性地裂解表达wt1的hla - a2.1阳性肿瘤细胞。其他研究小组也成功地产生了特异性裂解表达WT1的白血病细胞的ctl，并且不抑制在生理水平上表达WT1的正常造血细胞的集落形成。在小鼠体内系统中，用一种对含有H-2D(b)结合锚定基序的H-2D(b)分子具有较高结合亲和力的WT1肽免疫C57BL/6小鼠，诱导ctl以H-2D(b)限制的方式特异性裂解表达WT1的肿瘤细胞。此外，用WT1肽（肽疫苗）或WT1 cDNA （DNA疫苗）免疫的小鼠拒绝了表达WT1的肿瘤细胞的攻击，并且存活下来，没有迹象表明通过诱导的ctl对表达WT1的正常器官进行自身攻击。WT1蛋白已被确定为一种新的肿瘤抗原，最近的研究为开发基于WT1的过继T细胞疗法和针对各种恶性肿瘤的疫苗接种提供了理论依据。
Wild-type Wilms' tumor gene WT1 is expressed at high levels not only in most of acute myelocytic, acute lymphocytic, and chronic myelocytic leukemia, but also in various types of solid tumors including lung cancer. We tested the ability of the gene product (WT1) to serve as a target antigen for tumor -specific immunotherapy both in human in vitro system and mouse in vivo system. In the latter, we can evaluate the efficacy and the side effects of WT1 vaccination in vivo. In the human in vitro system, two WT1 peptides that contain HLA-A2.1 binding anchor motifs were determined to bind to HLA-A2.1 molecules. Peripheral blood mononuclear cells (PBMC) from an HLA-A2.1-psitive donor were repeatedly stimulated in vitro with TAP-deficient T2 cells pulsed with each of these two peptides, and CD8-positive cytotoxic T lymphocytes (CTLs) that specifically lyse WT1-expressing, HLA-A2.1-positive tumor cells were induced. Other groups also have succeeded in generating CTLs which specifically lyse WT1-expressing leukemia cells, and which do not inhibit colony-formation of normal hematopoietic cells that express WT1 at physiological levels. In the mouse in vivo system, immunization of C57BL/6 mice with one WT1 peptide with relatively high binding affinity for H-2D(b) molecules, which contain H-2D(b) binding anchor motifs, induced CTLs, which specifically lysed WT1-expressing tumor cells in an H-2D(b)-restricted manner. Furthermore, mice immunized with the WT1 peptide (peptide vaccination) or WT1 cDNA (DNA vaccination) rejected challenges by WT1-expressing tumor cells and survived with no signs of auto-aggression to WT1-expressing normal organs by the induced CTLs. The WT1 protein has been identified as a novel tumor antigen and recent investigations provide a rationale for developing WT1-based adoptive T cell therapy and vaccination against various kinds of malignant neoplasms.