Apostolopoulos Vasso, McKenzie Ian F C
The Austin Research Institiute, Studley Road, Heidelberg 3084, Victoria, Australia.
Crit Rev Immunol. 2017;37(2-6):421-437. doi: 10.1615/CritRevImmunol.v37.i2-6.110.
Mucins are attracting great interest as potential targets for immunotherapy in the development of vaccines for cancers expressing Mucinl (MUC1) (e.g., breast, pancreas, ovary, and others) as there is (1) a 10-fold increase in the amount in adenocarcinomas; (2) an alteration in expression where they become ubiquitous, and (3) due to altered glycosylation, new epitopes appear on the cell surface that are absent in normal tissues. These new epitopes can be carbohydrate; others are peptide in nature. The cloning of the cDNAs from mucins, particularly MUC1, has led to rapid advances being made, and it is clear that a highly immunogenic peptide exists within the variable number of tandem repeats (VNTR) found in all mucins. This peptide is immunogenic in mice, giving rise to strong antibody production, and most monoclonal antibodies made to breast cancer, which react with the protein core, react with the peptide APDTR. It is now also clear that humans with breast cancer have, in their draining lymph nodes, precursors of cytotoxic T cells that can be stimulated in vitro to react against breast cancer and indeed against the APDTR or a closely related peptide - shown from antibody-blocking studies. These CTLs are unique in that they are non-MHC restricted. The identification of suitable targets, coupled with the known immunogenicity of both the peptide and neo-carbohydrate epitopes, has led to the development of several different programs to immunize humans against breast cancer using either synthetic carbohydrates or peptides conjugated with adjuvants, and clinical trials are now in progress to evaluate their immunogenicity and anti-cancer effects.
粘蛋白作为表达粘蛋白1（MUC1）的癌症（如乳腺癌、胰腺癌、卵巢癌等）疫苗开发中免疫治疗的潜在靶点正引起极大关注，原因如下：（1）腺癌中其含量增加10倍；（2）表达改变，变得普遍存在；（3）由于糖基化改变，细胞表面出现正常组织中不存在的新表位。这些新表位可以是碳水化合物；其他的本质上是肽。粘蛋白cDNA的克隆，尤其是MUC1的克隆，取得了快速进展，很明显在所有粘蛋白的可变串联重复序列（VNTR）中存在一种高度免疫原性的肽。这种肽在小鼠中具有免疫原性，能产生强烈的抗体反应，大多数针对乳腺癌产生的、与蛋白质核心反应的单克隆抗体，都与肽APDTR反应。现在也清楚了，乳腺癌患者在其引流淋巴结中有细胞毒性T细胞前体，体外刺激这些前体可使其对乳腺癌产生反应，实际上也能对APDTR或密切相关的肽产生反应——抗体阻断研究已证实这一点。这些细胞毒性T细胞的独特之处在于它们不受主要组织相容性复合体（MHC）限制。合适靶点的确定，再加上已知肽和新碳水化合物表位的免疫原性，已促使开展了几个不同的项目，使用合成碳水化合物或与佐剂偶联的肽对人类进行乳腺癌免疫接种，目前正在进行临床试验以评估其免疫原性和抗癌效果。
