The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China.
Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, 350014, China; Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, 350014, Fujian Province, China.
Exp Cell Res. 2020 May 1;390(1):111953. doi: 10.1016/j.yexcr.2020.111953. Epub 2020 Mar 7.
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, MUC1, MUC1) 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), 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.
黏蛋白 1（MUC1）是一种在许多肿瘤类型中过度表达的肿瘤相关抗原（TAA），使其成为癌症免疫治疗的一个有吸引力的靶点。然而，这个标志物是一个没有高免疫原性的非突变抗原。在这项研究中，我们通过替换其序列中的氨基酸设计了几种新的改变肽，这些改变肽来源于低亲和力的 MUC1 肽，从而绕过免疫耐受。与野生型（WT）肽相比，改变的 MUC1 肽（MUC1、MUC1、MUC1）与 HLA-A0201 分子的亲和力更高，免疫原性更强。此外，这些改变的肽导致产生了更多的细胞毒性 T 淋巴细胞（CTL），这些 CTL 能够以 HLA-A0201 限制的方式交叉识别表达 WT MUC1 肽的胃癌细胞。此外，M1.1（MUC1）是一种已在多种肿瘤中进行测试的很有前途的抗肿瘤肽，它不能诱导更强的抗肿瘤反应。总之，我们的研究结果表明，MUC1 的改变肽作为潜在的 HLA-A0201 限制性 CTL 表位，可作为肽疫苗或构成肽负载树突状细胞疫苗的组成部分，用于胃癌治疗。
