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<p>HLA-bound peptides encoded by recurrent driver mutations are candidate targets for T cell-directed immunotherapy. Here we identify two neopeptides encoded by the <i>CTNNB1</i><sup>S37F</sup> mutation presented on the frequent HLA-A*02:01 and HLA-A*24:02 molecules in cell lines naturally expressing the mutation and <i>HLA</i> alleles. This mutation leads to a gain of function in β-catenin and is estimated to occur in &gt;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 <i>CTNNB1</i><sup>S37F+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月27日

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

摘要

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.