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

• 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; melanoma; peptide vaccine therapy; immune escape; HLA class I; TAP; LMP; cytotoxic T cell; HLA Class I; MICA

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是针对HLA-A2黑色素瘤患者免疫疗法的良好候选肽，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MART-1和HLA-A2在黑素细胞和CD8 T细胞浸润上的表达。 MART-1在大多数黑素细胞病变中表达，但在转移性病变中调节，而HLA-A2被黑色素瘤疾病进展下调。 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，这些表达与肽呈现给CdS T. T. T. cds T.此外，在黑色素瘤细胞中降低了与预后不良相关的MART-1和HLA-A2的调节。此外，IFN-GAMMA可以在培养的黑色素瘤细胞中诱导HLA I类，LMP和Tap分子的加强调节。这些数据表明，免疫从肽疗法中逃脱的机制如下：1）减少肽的调节，2）减少调节HLA I类或A2，3）下调LMP或TAP分子的调节。应分析黑色素瘤病变中的MART-1和HLA-A2表达，以选择有资格获得MART-1基于免疫疗法的患者，并监测具有抗T细胞疗法的黑色素瘤细胞的出现。