Functional up-regulation of human leukocyte antigen class I antigens expression by 5-aza-2′-deoxycytidine in cutaneous melanoma:: Immunotherapeutic implications
Functional up-regulation of human leukocyte antigen class I antigens expression by 5-aza-2′-deoxycytidine in cutaneous melanoma:: Immunotherapeutic implications
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DOI：
10.1158/1078-0432.ccr-06-3091
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发表时间：
2007-06-01
影响因子：
11.5
通讯作者：
Maio, Michele
中科院分区：
文献类型：
--
作者：
Fonsatti, Ester;Nicolay, Hugues J. M.;Maio, Michele
目的：研究DNA去甲基化试剂5 - 氮杂 - 2'-脱氧胞苷（5 - aza - CdR）提高针对黑素细胞分化抗原的免疫治疗方法有效性的潜力。
实验设计：通过实时逆转录 - PCR和间接免疫荧光（IIF）分析，研究5 - aza - CdR对11种人黑素瘤细胞系中gp100组成性表达的影响。通过对所研究的黑素瘤细胞进行IIF分析，研究5 - aza - CdR介导的人白细胞抗原（HLA）I类抗原和HLA - A2同种特异性、细胞间黏附分子 - 1（ICAM - 1）以及白细胞功能相关抗原 - 3表达水平的变化。通过铬 - 51释放试验、干扰素 - γ释放和干扰素 - γ ELISPOT试验，研究HLA - A2限制性gp100（209 - 217）特异性细胞毒性T淋巴细胞（CTL）对经或未经5 - aza - CdR处理的gp100阳性Mel 275黑素瘤细胞的识别。
结果：在所有研究的黑素瘤细胞中，gp100的组成性表达不受5 - aza - CdR影响。与未处理的细胞相比，Mel 275黑素瘤细胞暴露于5 - aza - CdR显著（P < 0.05）上调了其HLA I类抗原和ICAM - 1的表达。这些表型变化显著（P < 0.05）增加了gp100特异性CTL对经5 - aza - CdR处理的Mel 275黑素瘤细胞的裂解，并增加了其干扰素 - γ释放。对Mel 275细胞进行5 - aza - CdR处理还诱导更多的gp100特异性CTL分泌干扰素 - γ。
结论：5 - aza - CdR治疗通过上调HLA I类抗原表达，提高了gp100特异性CTL对黑素瘤细胞的识别；ICAM - 1也有助于这一现象。这些发现强调了5 - aza - CdR在与针对多种黑素瘤相关抗原的主动或过继性免疫治疗方法联合使用时具有更广泛的治疗意义。
Purpose: To investigate the potential of the DNA hypomethylating agent 5-aza-2'-deoxycytidine (5-aza-CdR) to improve the effectiveness of immunotherapeutic approaches against melanocyte differentiation antigens.Experimental Design: The effect of 5-aza-CdR on the constitutive expression of gp100 was investigated in 11 human melanoma cell lines by real-time reverse transcription-PCR and indirect immunofluorescence (IIF) analyses. 5-aza-CdR - mediated changes in the levels of expression of human leukocyte antigen (HLA) class I antigens and HLA-A2 allospecificity, intercellular adhesion molecule-1 (ICAM-1), and leukocyte-function - associated antigen-3 were investigated by IIF analysis on melanoma cells under study. The recognition of gp100-positive Mel 275 melanoma cells, treated or not with 5-aza-CdR, by HLA-A2- restricted gp100((209-217)) -specific CTL was investigated by Cr-51-release assays, IFN-gamma release and IFN-gamma ELISPOT assays.Results: The constitutive expression of gp100 was not affected by 5-aza-CdR on all melanoma cells investigated. Compared with untreated cells, the exposure of Mel 275 melanoma cells to 5-aza-CdR significantly (P < 0.05) up-regulated their expression of HLA class I antigens and of ICAM-1. These phenotypic changes significantly (P < 0.05) increased the lysis of 5-aza-CdR treated Mel 275 melanoma cells by gp100-specific CTL and increased their IFN-gamma release. 5-aza-CdR treatment of Mel 275 cells also induced a higher number of gp100-specific CTL to secrete IFN-gamma.Conclusions: Treatment with 5-aza-CdR improves the recognition of melanoma cells by gp100-specific CTL through the up-regulation of HLA class I antigens expression; ICAM-1 also contributes to this phenomenon. These findings highlight a broader range of therapeutic implications of 5-aza-CdR when used in association with active or adoptive immunotherapeutic approaches against a variety of melanoma-associated antigens.