Ludwig Institute for Cancer Research, Brussels Branch, Belgium.
Int J Cancer. 2011 Nov 15;129(10):2427-34. doi: 10.1002/ijc.25911. Epub 2011 Apr 20.
We have pursued our analysis of a melanoma patient who showed almost complete tumor regression following vaccination with MAGE-A1 and MAGE-A3 antigens. We previously described high frequencies of tumor-specific CTL precursors in blood samples collected after but also before vaccination. A set of CTL clones were derived that recognized antigens different from those of the vaccine. Two of these antigens were peptides encoded by another MAGE gene, MAGE-C2. Here we describe the antigen recognized by another tumor-specific CTL clone. It proved to be a third antigenic peptide encoded by gene MAGE-C2, ASSTLYLVF. It is presented by HLA-B57 molecules and proteasome-dependent. Tumor cells exposed to interferon-gamma (IFN-γ) were better recognized by the anti-MAGE-C2(42-50) CTL clone. This mainly resulted from a better processing of the peptide by the immunoproteasome as compared to the standard proteasome. Mass spectrometric analyses showed that the latter destroyed the antigenic peptide by cleaving between two internal hydrophobic residues. Despite its higher "chymotryptic-like" (posthydrophobic) activity, the immunoproteasome did not cleave at this position, in line with the suggestion that hydrophobic residues immediately downstream from a cleavage site impair cleavage by the immunoproteasome. We previously reported that one of the other MAGE-C2 peptides recognized by CTL from this patient was also better processed by the immunoproteasome. Together, these results support the notion that the tumor regression of this patient was mediated by an antitumor response shaped by IFN-γ and dominated by CTL directed against peptides that are better produced by the immunoproteasome, such as the MAGE-C2 peptides.
我们分析了一位黑色素瘤患者，他在接种 MAGE-A1 和 MAGE-A3 抗原后几乎完全消退了肿瘤。我们之前描述过，在接种前后的血液样本中，均检测到高频的肿瘤特异性 CTL 前体。我们从中分离出了一组能够识别与疫苗不同抗原的 CTL 克隆。其中两个抗原是另一个 MAGE 基因 MAGE-C2 编码的肽。在此，我们描述了另一个肿瘤特异性 CTL 克隆识别的抗原。它被证明是另一个由基因 MAGE-C2 编码的抗原肽，ASSTLYLVF。它由 HLA-B57 分子呈递，并依赖于蛋白酶体。与干扰素-γ（IFN-γ）共孵育的肿瘤细胞可被抗 MAGE-C2(42-50)CTL 克隆更好地识别。这主要是由于免疫蛋白酶体比标准蛋白酶体更好地加工该肽。质谱分析表明，后者通过在两个内部疏水性残基之间切割来破坏抗原肽。尽管免疫蛋白酶体的“糜蛋白酶样”（亲水性）活性较高，但它并未在此位置切割，这与疏水性残基紧邻切割位点会削弱免疫蛋白酶体切割的观点一致。我们之前报道过，该患者的另一个由 CTL 识别的 MAGE-C2 肽也被免疫蛋白酶体更好地加工。这些结果共同表明，该患者的肿瘤消退是由 IFN-γ 介导的抗肿瘤反应介导的，该反应主要由针对免疫蛋白酶体更好产生的肽（如 MAGE-C2 肽）的 CTL 主导。
