Antigen Spreading Contributes to MAGE Vaccination-Induced Regression of Melanoma Metastases
Antigen Spreading Contributes to MAGE Vaccination-Induced Regression of Melanoma Metastases
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DOI：
10.1158/0008-5472.can-10-2693
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发表时间：
2011-02-15
期刊：
影响因子：
11.2
通讯作者：
Coulie, Pierre G.
中科院分区：
文献类型：
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作者：
Corbiere, Veronique;Chapiro, Jacques;Coulie, Pierre G.
癌症免疫治疗的核心挑战是了解人类患者有效疫苗应答的基础。在之前的工作中，我们发现了一名黑色素瘤患者，在接种黑色素瘤抗原（法师）后，血液中显示出低水平的抗疫苗溶细胞T细胞（CTL）反应，肿瘤消退。使用包括T细胞受体β（TCR β）cDNA库在内的遗传方法，我们在消退的转移瘤中发现了很少的抗疫苗CTL。然而，发现了更多数量的TCR β序列，其中几个对应于对非疫苗肿瘤抗原具有特异性的CTL克隆，这表明抗原扩散发生在消退转移中。在这项研究中，我们发现了另一种属于肿瘤特异性CTL的TCR，其富集于消退转移中，并且仅在接种疫苗后才在血液中检测到。我们使用TCR β序列从患者分离的肿瘤浸润淋巴细胞中检测和克隆所需的T细胞。该CD 8克隆特异性裂解自体黑素瘤细胞并显示HLA-A2限制。其靶抗原被鉴定为线粒体酶酪蛋白分解蛋白酶。靶抗原基因在肿瘤中发生突变，导致产生新抗原。由于免疫蛋白酶体对抗原肽的优先加工，IFN-γ处理增加了CTL对黑素瘤细胞的裂解。这些结果表明，患者的肿瘤排斥效应物确实是对非疫苗肿瘤特异性抗原的CTL应答，进一步支持了我们的假设。在这些抗原中，我们发现的突变抗原是唯一在接种疫苗前不能检测到T细胞的抗原。我们认为，抗肿瘤T细胞对真正的肿瘤特异性抗原的反应的抗原扩散对肿瘤消退有决定性的作用。Cancer Res; 71（4）; 1253-62.（C）2011年《非洲标准化评论》。
A core challenge in cancer immunotherapy is to understand the basis for efficacious vaccine responses in human patients. In previous work we identified a melanoma patient who displayed a low-level antivaccine cytolytic T-cell (CTL) response in blood with tumor regression after vaccination with melanoma antigens (MAGE). Using a genetic approach including T-cell receptor beta (TCR beta) cDNA libraries, we found very few antivaccine CTLs in regressing metastases. However, a far greater number of TCR beta sequences were found with several of these corresponding to CTL clones specific for nonvaccine tumor antigens, suggesting that antigen spreading was occurring in regressing metastases. In this study, we found another TCR belonging to tumor-specific CTL enriched in regressing metastases and detectable in blood only after vaccination. We used the TCR beta sequence to detect and clone the desired T cells from tumor-infiltrating lymphocytes isolated from the patient. This CD8 clone specifically lysed autologous melanoma cells and displayed HLA-A2 restriction. Its target antigen was identified as the mitochondrial enzyme caseinolytic protease. The target antigen gene was mutated in the tumor, resulting in production of a neoantigen. Melanoma cell lysis by the CTL was increased by IFN-gamma treatment due to preferential processing of the antigenic peptide by the immunoproteasome. These results argue that tumor rejection effectors in the patient were indeed CTL responding to nonvaccine tumor-specific antigens, further supporting our hypothesis. Among such antigens, the mutated antigen we found is the only antigen against which no T cells could be detected before vaccination. We propose that antigen spreading of an antitumor T-cell response to truly tumor-specific antigens contributes decisively to tumor regression. Cancer Res; 71(4); 1253-62. (C)2011 AACR.