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）黑色素瘤病变中HLA I类下调的频率是这项研究的目的是研究HLA I类抗原在外科手术去除的黑色素瘤病变中的表达。在此末端，在免疫过氧化物酶反应中用单克隆抗体（MAB）染色了32个原发性病变和11个转移性病变。将黑色素瘤细胞染色的强度与肿瘤巢周围的角质形成细胞的染色强度进行了比较。使用常规淋巴细胞毒性测定法确定患者的HLA表型。大约20％的原发性和约50％的转移性病变未染色或用MAB降低的强度染色或单态特异性抗原确定剂。此外，大约40％的原发性病变和大约60％的转移性病变没有染色或用低强度染色，通过mAb至HLA I类同种特定性。这些结果表明，HLA I类A类异常的频率…更多的NTOGEN表达在黑色素瘤病变中很高。这些异常可能会对基于T细胞的免疫疗法产生负面影响，因为它们为黑素毒素T细胞提供了一种机制，可通过细胞毒性T细胞逃避破坏。（2）HLA I类下调的机械在黑色素瘤细胞中的机械。通过黑色素瘤病变中的免疫过氧化物酶染色测试，因为这些分子在呈现黑色素瘤相关的抗原衍生肽与细胞毒性T细胞的表现中起重要作用。在原发性病变和转移性病变中，LMP2的表达频率低于LMP7。 TAP1，TAP2和HLA I类抗原表达在转移性中比原发性黑色素瘤病变更频繁地下调。在大约60％的原发性和转移性黑色素瘤病变中观察到TAP1，TAP2和HLA I类抗原表达的同步下调。此外，这些原发性病变中的这些下调与疾病的厚度显着相关，疾病的进展时间减少了，生存率降低。这些结果表明，TAP在黑色素瘤细胞的HLA I类下调和疾病的临床过程中起着重要作用，这可能是通过为黑色素瘤细胞提供一种在疾病进展过程中逃脱CTL识别的机制。较少的