The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
Eur J Immunol. 2023 May;53(5):e2250054. doi: 10.1002/eji.202250054. Epub 2023 Feb 28.
High-frequency mutation of the TP53 tumor suppressor gene is observed in multiple human cancers, which promotes cancer progression. However, the mutated gene-encoded protein may serve as a tumor antigen to elicit tumor-specific immune responses. In this study, we detected widespread expression of shared TP53-Y220C neoantigen in hepatocellular carcinoma with low affinity and low stability of binding to HLA-A0201 molecules. We substituted the amino acid sequences VVPCEPPEV with VLPCEPPEV in the TP53-Y220C neoantigen to yield a TP53-Y220C (L2) neoantigen. This altered neoantigen was found to increase affinity and stability and induce more cytotoxic T lymphocytes (CTLs), indicating improvements in immunogenicity. In vitro assays showed the cytotoxicity of CTLs stimulated by both TP53-Y220C and TP53-Y220C (L2) neoantigens against multiple HLA-A0201-positive cancer cells expressing TP53-Y220C neoantigens; however, the TP53-Y220C (L2) neoantigen showed higher cytotoxicity than the TP53-Y220C neoantigen against cancer cells. More importantly, in vivo assays demonstrated greater inhibition of hepatocellular carcinoma cell proliferation by TP53-Y220C (L2) neoantigen-specific CTLs relative to TP53-Y220C neoantigen in zebrafish and nonobese diabetic/severe combined immune deficiency mouse models. The results of this study demonstrate enhanced immunogenicity of the shared TP53-Y220C (L2) neoantigen, which has the potential as dendritic cells or peptide vaccines for multiple cancers.
TP53 肿瘤抑制基因的高频突变在多种人类癌症中被观察到，这促进了癌症的进展。然而，突变基因编码的蛋白质可能作为肿瘤抗原，引发肿瘤特异性免疫反应。在这项研究中，我们检测到低亲和力和低稳定性与 HLA-A0201 分子结合的广泛表达的共享 TP53-Y220C 新抗原在肝细胞癌中。我们用 VLPCEPPEV 取代了 TP53-Y220C 新抗原中的 VVPCEPPEV 氨基酸序列，得到了 TP53-Y220C（L2）新抗原。这种改变的新抗原被发现增加了亲和力和稳定性，并诱导更多的细胞毒性 T 淋巴细胞（CTL），表明其免疫原性得到了改善。体外实验表明，由 TP53-Y220C 和 TP53-Y220C（L2）新抗原刺激的 CTL 对多个表达 TP53-Y220C 新抗原的 HLA-A0201 阳性癌细胞具有细胞毒性；然而，TP53-Y220C（L2）新抗原对癌细胞的细胞毒性高于 TP53-Y220C 新抗原。更重要的是，体内实验表明，与 TP53-Y220C 新抗原相比，TP53-Y220C（L2）新抗原特异性 CTL 对肝癌细胞增殖的抑制作用更强在斑马鱼和非肥胖糖尿病/严重联合免疫缺陷小鼠模型中。这项研究的结果表明，共享的 TP53-Y220C（L2）新抗原具有增强的免疫原性，有可能作为树突状细胞或肽疫苗用于多种癌症。
