STUDY ON MACHINERY HLA CLASS I DOWNREGULATION ON MELANOMA CELLS.

黑色素瘤细胞 HLA I 类下调机制的研究。

基本信息

批准号：
09670888
负责人：
KAGESHITA Toshiro
金额：
$ 1.66万
依托单位：
KUMAMOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670888/
关键词：
MELANOMA HLA CLASS I LMP TAP HlaClassI HlaClassI allete HLS Class I allele

项目摘要

(1) Frequency of HLA Class I downregulation in melanoma lesionsThe aim of this study was to investigate the expression of HLA Class I antigens in surgically removed melanoma lesions. To this end 32 primary and 11 metastatic lesions were stained in the immunoperoxidase reaction with monoclonal antibodies(mAb) to monomorphic, locus specific and polymorphic antigenic determinants. The intensity of staining of melanoma cells was compared to that of keratinocytes surrounding the tumor nest. The patients' HLA phenotype was determined utilizing the conventional lymphocytotoxicity assay. About 20% of primary and about 50% of metastatic lesions were not stained or were stained with reduced intensity by mAb to monomorphic and locus specific antigenic determinants. Moreover about 40% of primary and about 60% of metastatic lesions were not stained or were stained with low intensity, by mAb to HLA Class I allospecificities. These results indicate that the frequency of abnormalities in HLA Class I a … More ntigen expression is high in melanoma lesions. These abnormalities are likely to have a negative impact on T cell based immunotherapy, since they provide melanoma cells with a mechanism to escape from destruction by cytotoxic T cells.(2) Machinery of HLA Class I downregulation in melanoma cells.The expression of the proteasome subunits LMP2 and LMP7, the MHC-encoded transporter subunits TAP1 and TAP2 and HLA Class antigens was tested by immunoperoxidase staining in melanoma lesions, since these molecules play an important role in the presentation of melanoma associated antigen derived peptides to cytotoxic T cells. LMP2 was less frequentlt expressed than LMP7 in primary and metastatic lesions. TAP1, TAP2 and HLA Class I antigen expression was more frquently downregulated in metastatic than in primary melanoma lesions. A synchronous downregulation of TAP1, TAP2 and HLA Class I antigen expression was observed in about 60% of primary and metastatic melanoma lesions. Moreover, these downregulation in primary lesions was significantly associated with their thickness, with the stage of the disease, with a reduced time to disease progression and with a reduced survival. These results suggest that TAP plays an important role in HLA Class I downregulation in melanoma cells and in the clinical course of the disease, probably by providing melanoma cells with a mechanism to escape from CTL recognition during disease progression. Less

（1）研究中HLA I类下调的频率是研究HLA类直肠的表达与单态，多态性的抗原抗原性测定，比较了肿瘤巢周围的thatinoc thatiencics，使用了50％的转移性淋巴细胞，并确定了肿瘤巢周围的thatinoc yts。在大约40％的原发性和60％的转移性病变上，单态和基因座的抗原决定性并未染成HLA I类同种疗法。对基于T细胞的免疫疗法的影响是通过细胞毒性T细胞从设计中的机制，E亚基LMP2和LMP7，MHC编码的转运蛋白亚基TAP1和TAP2和Hlassass抗原在分子中的重要作用黑色素瘤与细胞毒性T型抗原相关的LMP2在原发性病变和转移性病变中的频率较低。原发性和转移性黑色素瘤病变的百分比。疾病的病程，可能是通过为黑色素瘤细胞提供一种机制，以避免在不断发展过程中逃脱CTL识别。