Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine
Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine
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DOI：
10.1073/pnas.1115166109
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发表时间：
2012-01-03
影响因子：
11.1
通讯作者：
Boons, Geert-Jan
中科院分区：
文献类型：
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作者：
Lakshminarayanan, Vani;Thompson, Pamela;Boons, Geert-Jan
粘蛋白MUC 1通常被上皮癌细胞异常糖基化，表现为截短的O-连接的α-淀粉酶。所得到的糖肽表位可以结合细胞表面主要组织相容性复合物（MHC）分子并且易于被细胞毒性T淋巴细胞（CTL）识别，而肿瘤细胞表面上的异常糖基化MUC 1蛋白可以被抗体结合以介导抗体依赖性细胞介导的细胞毒性（ADCC）。当非糖基化MUC 1序列用于疫苗接种时，引发针对癌症表达的MUC 1的CTL和IgG抗体的努力尚未成功，这可能是由于构象差异。由于对抗原加工的敏感性受损，用密集糖基化MUC 1肽进行免疫也是无效的。考虑到免疫靶向肿瘤相关MUC 1的挑战，我们已经确定了在乳腺癌小鼠模型中持续诱导特异性针对肿瘤形式MUC 1的CTL和ADCC介导抗体的最低要求，从而产生治疗反应。该疫苗由免疫佐剂Pam 3CysSK 4、肽Thelper表位和异常糖基化的MUC 1肽组成。三种组分的共价连接对于最大功效是必不可少的。该疫苗产生的CTL既识别糖基化肽又识别非糖基化肽，而类似的非糖基化疫苗产生的CTL仅识别非糖基化肽。与未糖基化的对照相比，糖基化的三联疫苗引起的抗体显著更具裂解性。结果，用糖基化三联疫苗免疫在肿瘤预防方面是上级的。除了其自身作为临床靶点的适用性外，MUC 1的这些研究可能预测适用于许多其他肿瘤相关抗原的共价连接策略。
The mucin MUC1 is typically aberrantly glycosylated by epithelial cancer cells manifested by truncated O-linked saccharides. The resultant glycopeptide epitopes can bind cell surface major histocompatibility complex (MHC) molecules and are susceptible to recognition by cytotoxic T lymphocytes (CTLs), whereas aberrantly glycosylated MUC1 protein on the tumor cell surface can be bound by antibodies to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). Efforts to elicit CTLs and IgG antibodies against cancer-expressed MUC1 have not been successful when nonglycosylated MUC1 sequences were used for vaccination, probably due to conformational dissimilarities. Immunizations with densely glycosylated MUC1 peptides have also been ineffective due to impaired susceptibility to antigen processing. Given the challenges to immuno-target tumor-associated MUC1, we have identified the minimum requirements to consistently induce CTLs and ADCC-mediating antibodies specific for the tumor form of MUC1 resulting in a therapeutic response in a mouse model of mammary cancer. The vaccine is composed of the immunoadjuvant Pam3CysSK4, a peptide Thelper epitope and an aberrantly glycosylated MUC1 peptide. Covalent linkage of the three components was essential for maximum efficacy. The vaccine produced CTLs, which recognized both glycosylated and nonglycosylated peptides, whereas a similar nonglycosylated vaccine gave CTLs which recognized only nonglycosylated peptide. Antibodies elicited by the glycosylated tripartite vaccine were significantly more lytic compared with the unglycosylated control. As a result, immunization with the glycosylated tripartite vaccine was superior in tumor prevention. Besides its own aptness as a clinical target, these studies of MUC1 are likely predictive of a covalent linking strategy applicable to many additional tumor-associated antigens.