MUC1 is a tumor-associated antigen (TAA) overexpressed in many tumor types, which makes it an attractive target for cancer immunotherapy. However, this marker is a non-mutated antigen without high immunogenicity. In this study, we designed several new altered peptides by replacing amino acids in their sequences, which were derived from a low-affinity MUC1 peptide, thus bypassing immune tolerance. Compared to the wild-type (WT) peptide, the altered MUC1 peptides (MUC1_1081-1089L2, MUC1_1156-1164L2, MUC1_1068-1076Y1) showed higher affinity to the HLA-A0201 molecule and stronger immunogenicity. Furthermore, these altered peptides resulted in the generation of more cytotoxic T lymphocytes (CTLs) that could cross-recognize gastric cancer cells expressing WT MUC1 peptides, in an HLA-A0201-restricted manner. In addition, M1.1 (MUC1_950-958), a promising antitumor peptide that has been tested in multiple tumors, was not able to induce stronger antitumor responses. Collectively, our results demonstrated that altered peptides from MUC1, as potential HLA-A0201-restricted CTL epitopes, could serve as peptide vaccines or constitute components of peptide-loaded dendritic cell vaccines for gastric cancer treatment.

MUC1是在许多肿瘤类型中过表达的肿瘤相关抗原（TAA），这使其成为癌症免疫疗法的诱人靶标。但是，该标志物是没有高免疫原性的非突变抗原。在这项研究中，我们通过替换序列中的氨基酸（从低亲和性MUC1肽衍生而来），设计了几种新的修饰肽，从而绕开了免疫耐受性。与野生型（WT）肽相比，改变后的MUC1肽（MUC1 _1081-1089L2，MUC1 _1156-1164L2，MUC1 _1068-1076Y1）显示出对HLA-A0201分子的更高亲和力和更强的免疫原性。此外，这些改变的肽导致产生更多的细胞毒性T淋巴细胞（CTL），它们可以以HLA-A0201限制的方式交叉识别表达WT MUC1肽的胃癌细胞。另外，已经在多种肿瘤中测试的有希望的抗肿瘤肽M1.1（MUC1 _950-958）不能诱导更强的抗肿瘤反应。总的来说，我们的结果表明，作为潜在的HLA-A0201限制性CTL表位，MUC1改变的肽可以用作肽疫苗或构成用于胃癌治疗的载有肽的树突状细胞疫苗的组成部分。