Analysis of Immune Escape from Melanoma Peptide Vaccine Therapy

黑色素瘤肽疫苗治疗的免疫逃逸分析

基本信息

批准号：
12670828
负责人：
KAGESHITA Toshiro
金额：
$ 2.05万
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：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670828/
关键词：
melanoma peptide vaccine therapy immune escape HLA class I TAP LMP cytotoxic T cell HLA Class I MICA

项目摘要

MART-1 is a good candidate peptide for immunotherapy against HLA-A2 patients with melanoma, since it is a highly immunogenic antigen recognized by HLA-A2 cytotoxic T cells and expressed in the majority of melanoma lesions. In the present study, the expression of MART-1 and HLA-A2 on melanocytic cells and CD8 T cell infiltrate was analyzed. MART-1 was expressed in most of melanocytic lesions but it was down regulated in metastatic lesions, while HLA-A2 was downregulated with melanoma disease progression. CD8 T cell infiltrate was closely associated with HLA-A2 expression on melanoma cell. Expression of HLA-A2 was significantly associated with the expression of LMP and TAP molecules, which are involved in peptide presentation to CDS T. Furthermore, concomitnt down regulation of MART-1 and HLA-A2 in melanoma cells correlated with poor prognosis. In addition, IFN-gamma could induce the up regulation of HLA class I, LMP and TAP molecules in cultured melanoma cells. These data suggest that the mechanisms of immune escape from peptide therapy are as follows : 1) down regulation of peptide, 2) down regulation of HLA class I or A2, 3) down regulation of LMP or TAP molecules. MART-1 and HLA-A2 expression in melanoma lesions should be analyzed for selection of the patients eligible for MART-1 based immunotherapy and monitoring emerge of melanoma cells resistant to T cell therapy.

MART-1 是 HLA-A2 黑色素瘤患者免疫治疗的良好候选肽，因为它是 HLA-A2 细胞毒性 T 细胞识别的高度免疫原性抗原，并在大多数黑色素瘤病变中表达。在本研究中，分析了黑素细胞和 CD8 T 细胞浸润上 MART-1 和 HLA-A2 的表达。 MART-1在大多数黑色素细胞病变中表达，但在转移性病变中表达下调，而HLA-A2随着黑色素瘤疾病进展而下调。 CD8 T 细胞浸润与黑色素瘤细胞上的 HLA-A2 表达密切相关。 HLA-A2 的表达与 LMP 和 TAP 分子的表达显着相关，这些分子参与向 CDS T 的肽呈递。此外，黑色素瘤细胞中 MART-1 和 HLA-A2 的同时下调与不良预后相关。此外，IFN-γ可以诱导培养的黑色素瘤细胞中HLA I类、LMP和TAP分子的上调。这些数据表明肽治疗的免疫逃逸机制如下：1）肽的下调，2）HLA I 类或 A2 类的下调，3）LMP 或 TAP 分子的下调。应分析黑色素瘤病灶中的 MART-1 和 HLA-A2 表达，以选择适合接受基于 MART-1 的免疫治疗的患者，并监测对 T 细胞治疗产生耐药性的黑色素瘤细胞的出现。