Department of Biochemistry, Mayo Clinic College of Medicine and Mayo Clinic Comprehensive Cancer Center, Scottsdale, AZ 85259, USA.
Proc Natl Acad Sci U S A. 2012 Jan 3;109(1):261-6. doi: 10.1073/pnas.1115166109. Epub 2011 Dec 14.
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 Pam(3)CysSK(4), a peptide T(helper) 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.
黏蛋白 MUC1 通常在肿瘤细胞中发生异常糖基化，表现为 O 连接聚糖的截断。由此产生的糖肽表位可以与细胞表面主要组织相容性复合体（MHC）分子结合，并容易被细胞毒性 T 淋巴细胞（CTL）识别，而肿瘤细胞表面异常糖基化的 MUC1 蛋白可以与抗体结合，介导抗体依赖的细胞介导的细胞毒性（ADCC）。当使用非糖基化 MUC1 序列进行疫苗接种时，针对癌症表达的 MUC1 诱导 CTL 和 IgG 抗体的努力并未成功，这可能是由于构象差异所致。由于抗原加工的敏感性受损，用高度糖基化的 MUC1 肽进行免疫接种也没有效果。鉴于免疫靶向肿瘤相关 MUC1 的挑战，我们已经确定了始终诱导针对肿瘤形式的 MUC1 的 CTL 和 ADCC 介导的抗体的最低要求，从而在乳腺癌小鼠模型中产生治疗反应。该疫苗由免疫佐剂 Pam(3)CysSK(4)、T 辅助表位肽和异常糖基化 MUC1 肽组成。三个成分的共价连接对于最大功效至关重要。该疫苗产生了 CTL，其可识别糖基化和非糖基化肽，而类似的非糖基化疫苗则产生仅识别非糖基化肽的 CTL。糖基化三聚体疫苗引发的抗体比未糖基化的对照抗体具有更高的细胞毒性。因此，与未糖基化对照相比，用糖基化三聚体疫苗进行免疫接种在肿瘤预防方面更有效。除了作为临床靶点的自身适宜性外，这些 MUC1 研究可能预测了一种适用于许多其他肿瘤相关抗原的共价连接策略。
