CTNNB1S37F (CTNNB1WT encodes β-catenin) is a driver mutation found across solid tumors. Using an HLA+ cell line transduced with CTNNB1S37F, Eggebø et al. used MS to identify two HLA-bound neopeptides that were also expressed naturally on CTNNB1S37F+ tumor cells. Priming naive CD8+ T cells with these neoantigens identified 4 reactive TCRs that were highly specific, recognizing CTNNB1S37F with pM-nM affinity, but not CTNNB1WT or similar off-target peptides. TCR T cells expressing these TCRs eliminated patient-derived tumor organoids in vitro, and effectively treated CTNNB1S37F+ melanoma and PDX endometrial adenocarcinoma in vivo.
Contributed by Alex Najibi
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.
Author Info: (1) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (2) Department
Author Info: (1) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (2) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (3) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (4) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (5) The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway. (6) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (7) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (8) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (9) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (10) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (11) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (12) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (13) The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. fridtjl@medisin.uio.no. Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway. fridtjl@medisin.uio.no. (14) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. m.m.nielsen@medisin.uio.no. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. m.m.nielsen@medisin.uio.no. (15) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. johanna.olweus@medisin.uio.no. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. johanna.olweus@medisin.uio.no.
