EARLY DETECTION OF THE METASTASIS AND IMMUNETHERAPY TARGETING TUMOR-REJECTION ANTIGENS IN HUMAN HEPATOCELLULARA CARCINOMA

人肝细胞癌转移的早期检测和针对肿瘤排斥抗原的免疫治疗

基本信息

批准号：
10670474
负责人：
HIGASHI Toshihiro
金额：
$ 2.11万
依托单位：
OKAYAMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670474/
关键词：
TUMOR-REJECTION GENE CANCER-TESTIS ANTIGEN HCC VACCINE THERAPY がん退縮抗原

项目摘要

We have clarified that tumor-rejection antigens such as MAGE-1, MAGE-3 and NY-ESO-1 are expressed in a significant proportion of human hepatocellular carcinoma(HCC)at mRNA and protein levels. These genes are not expressed normal somatic cells except for testis. Although we have attempted to detect cytotoxic T-cell responses against MAGE-3 or NY-ESO-1 derived peplides in HLA-A2 positive healthy volunteers and HCC patients, we could not detect it to date. Since it has been reported that CTL activity against NY-ESO-1 was detected in melanoma patients in whom IgG antibodies against NY-ESO-1 was found in serum, we have also tried to detect serum antibodies in HCC patients. As a result, the IgG antibodies were observed in two of 100 patients with HCC.This result suggests that immune response against NY-ESO-1 is developed in HCC patients and NY-ESO-1 derived peptides can be used for vaccine therapy in HCC patients. In contrast, we have analyzed the expression of antigen-processing and antigen-presenting molecules, e.g., LMP-2, -7, Heat shock protein, TAP, β2-microglobulin, HLA class-I and B7-1 and -2. We have clarified that the expression of co-stimulatory molecules, B7-1 and -2 was lost in a significant proportion of HCC and that of HLA class-I molecule was also reduced in less frequency. These results indicate that HCC escape from immune surveillance via the losses of these molecules especially via the loss of B7 molecules. For the next step for immunotherapy in HCC patients, we have to determine whether the transfection of B7 molecules in dendritic cells as APC or HCC cells as the target cells can elicit CTL responses against tumor-rejection antigens. Further, we have carried out SEREX and identified four molecules are aberrantly expressed in HCC.We are also examining the expression of OY-TES-1 gene in human HCC samples, which was discovered as one of cancer-testis antigens in our university.

我们已经澄清说，在mRNA和蛋白质水平上，肿瘤抑制抗原（例如MAGE-1，MAGE-3和NY-ESO-1）以很大比例的人肝细胞癌（HCC）表达。除睾丸以外，这些基因不表达正常的体细胞。尽管我们试图检测针对HLA-A2阳性健康志愿者和HCC患者的MAGE-3或NY-ESO-1衍生的peplides的细胞毒性T细胞反应，但我们无法检测到它迄今为止。由于据报道，在黑色素瘤患者中发现了针对NY-ESO-1的CTL活性，其中在血清中发现了针对NY-ESO-1的IgG抗体，我们还试图检测HCC患者的血清抗体。结果，在100例HCC患者中，有两名IgG抗体。这表明在HCC患者中开发了针对NY-ESO-1的免疫反应，并且可以将NY-ESO-1衍生的Petides用于HCC患者的疫苗治疗。相比之下，我们已经分析了抗原加工和抗原呈递分子的表达，例如LMP-2，-7，热休克蛋白，TAP，β2-微球蛋白，HLA类-I类和B7-1和-2。我们已经澄清说，共刺激分子B7-1和-2的表达在很大一部分的HCC中丢失，而HLA I类分子的表达也以较小的频率降低。这些结果表明，HCC通过这些分子的损失，尤其是通过B7分子的损失而摆脱免疫监视。对于HCC患者免疫疗法的下一步，我们必须确定树突状细胞中B7分子作为APC或HCC细胞的翻译是否可以引起针对肿瘤排斥抗原的CTL反应。此外，我们已经进行了SEREX，并在HCC中鉴定出四个分子在HCC中异常表达。我们还研究了人类HCC样品中OY-TES-1基因的表达，该样品被发现是我们大学中的癌症疫苗抗原之一。