Analysis of Immune Escape from Melanoma Peptide Vaccine Therapy

MART-1是针对患有黑色素瘤的HLA-A2患者的免疫疗法的良好候选肽，因为它是由HLA-A2细胞毒性T细胞识别的高度免疫原性抗原，并且在大多数黑色素瘤病变中表达。在本研究中，MART-1和HLA-A2在黑素细胞和CD 8 T细胞浸润上的表达进行了分析。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。CD 8 T细胞浸润与HLA-A2表达密切相关。HLA-A2的表达与LMP和TAP分子的表达显著相关，这两种分子参与了向CDS T的肽呈递。此外，MART-1和HLA-A2在黑色素瘤细胞中的伴随下调与不良预后相关。此外，IFN-γ可诱导培养的黑素瘤细胞中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的下调，3）LMP或TAP分子的下调。应分析黑色素瘤病变中MART-1和HLA-A2的表达，以选择适合基于MART-1的免疫治疗的患者，并监测黑色素瘤细胞对T细胞治疗的耐药性的出现。

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.