biostudies-literatureShafer PNHLBI NIH HHSNCI NIH HHSNIGMS NIH HHSNIH HHS266-275https://www.ebi.ac.uk/biostudies/studies/S-EPMC10922969biostudies-literatureUnknown26(3)T cell receptor engineered T cell (TCR T) therapies have shown recent efficacy against certain types of solid metastatic cancers. However, to extend TCR T therapies to treat more patients across additional cancer types, new TCRs recognizing cancer-specific antigen targets are needed. Driver mutations in AKT1, ESR1, PIK3CA, and TP53 are common in patients with metastatic breast cancer (MBC) and if immunogenic could serve as ideal tumor-specific targets for TCR T therapy to treat this disease. Through IFN-γ ELISpot screening of in vitro expanded neopeptide-stimulated T cell lines from healthy donors and MBC patients, we identified reactivity towards 11 of 13 of the mutations. To identify neopeptide-specific TCRs, we then performed single-cell RNA sequencing of one of the T cell lines followiCytotherapyIncongruity between T cell receptor recognition of breast cancer hotspot mutations ESR1 Y537S and D538G following exogenous peptide loading versus endogenous antigen processing.PMC10922969S10 OD025240R01 CA072038T32 GM136554T32 HL092332P50 CA058183S10 OD023469R37 CA248478Woods MChoi JMRodriguez-Plata CMRooney CMaknojia AShafer PFuqua SHoyos VLeung WKManliguez ABurt BLee HSMosquera ASomes LKJoubert JZhang BLeen AMRanjan RfalseIncongruity between T cell receptor recognition of breast cancer hotspot mutations ESR1 Y537S and D538G following exogenous peptide loading versus endogenous antigen processing.T cell receptor engineered T cell (TCR T) therapies have shown recent efficacy against certain types of solid metastatic cancers. However, to extend TCR T therapies to treat more patients across additional cancer types, new TCRs recognizing cancer-specific antigen targets are needed. Driver mutations in AKT1, ESR1, PIK3CA, and TP53 are common in patients with metastatic breast cancer (MBC) and if immunogenic could serve as ideal tumor-specific targets for TCR T therapy to treat this disease. Through IFN-γ ELISpot screening of in vitro expanded neopeptide-stimulated T cell lines from healthy donors and MBC patients, we identified reactivity towards 11 of 13 of the mutations. To identify neopeptide-specific TCRs, we then performed single-cell RNA sequencing of one of the T cell lines followi2024-01-01T00:00:00Z2024 Mar2025-04-04T00:48:07.914Z2025-04-04T00:48:07.914ZS-EPMC109229693823116510.1016/j.jcyt.2023.12.002