挪威奥斯陆大学Johanna Olweus团队的研究显示，靶向共享β-连环蛋白突变的TCR工程T细胞可根除实体肿瘤。相关论文发表在2025年8月27日出版的《自然—免疫学》杂志上。

在此，该团队在自然表达突变和HLA等位基因的细胞系中发现了两个由CTNNB1^S37F突变编码的新肽，这些突变存在于HLA-A*02:01和HLA-A*24:02分子中。这种突变导致β-连环蛋白的功能增加，据估计，在美国每年有7000例新的癌症病例发生这种突变。特异性识别突变肽的T细胞受体（TCRs）是从原始健康供体T细胞中分离出来的。用CTNNB1-S37F TCRs重定向的T细胞在体外有效地杀死CTNNB1^S37F+细胞系和患者来源的类器官，并在自然表达突变和限制性HLA的黑色素瘤细胞系小鼠模型和患者来源的子宫内膜腺癌异种移植模型中根除已建立的肿瘤。研究组提出靶向CTNNB1-S37F的TCR-T细胞可以作为实体癌免疫治疗的基础。

研究人员表示，由复发性驱动突变编码的HLA结合肽是T细胞定向免疫治疗的候选靶点。

附：英文原文

Title: TCR-engineered T cells targeting a shared β-catenin mutation eradicate solid tumors

Author: Eggeb, Maria Stadheim, Heinzelbecker, Julia, Palashati, Heyilimu, Chandler, Nicholas, Tran, Trung The, Li, Yingqian, Yang, Weiwen, Laos, Maarja, Blaas, Isaac, Rustad, Even Holth, Bollineni, Ravi Chand, Delic-Sarac, Marina, Lund-Johansen, Fridtjof, Nielsen, Morten Milek, Olweus, Johanna

Issue&Volume: 2025-08-27

Abstract: HLA-bound peptides encoded by recurrent driver mutations are candidate targets for T cell-directed immunotherapy. Here we identify two neopeptides encoded by the CTNNB1S37F mutation presented on the frequent HLA-A*02:01 and HLA-A*24:02 molecules in cell lines naturally expressing the mutation and HLA alleles. This mutation leads to a gain of function in β-catenin and is estimated to occur in >7,000 new cancer cases annually in the United States. T cell receptors (TCRs) that specifically recognize the mutant peptides were isolated from naive healthy donor T cells. T cells redirected with CTNNB1-S37F TCRs efficiently killed CTNNB1S37F+ cell lines and patient-derived organoids in vitro and eradicated established tumors in a melanoma cell line mouse model and a patient-derived xenograft model of endometrial adenocarcinoma naturally expressing the mutation and the restricting HLA. We propose that TCR-T cells targeting CTNNB1-S37F can serve as a basis for solid cancer immunotherapy.

DOI: 10.1038/s41590-025-02252-1

Source: https://www.nature.com/articles/s41590-025-02252-1