Anti-HER2/neu TCR-T Cells in Action: linking transcriptional signatures, secretomics, and

Introduction: T cell receptor-engineered T cell therapy has emerged as a promising approach in cancer immunotherapy, leveraging the ability of T cells to recognize tumor antigens presented on major histocompatibility complex molecules, offering a targeted approach for treating cancers. This study advances previous research conducted at the Laboratory of Molecular Immunology at RIFCI, where the full repertoire of HER2/neu-specific TCRs was identified. Specifically, here we are functionally validating a distinct TCR clonotype targeting the KIFGSLAFL peptide of HER2/neu protein presented by the HLA-A*02. Methods: We employed an integrated approach combining Results: Anti-HER2/neu TCR-T cells exhibited robust antigen-specific cytotoxicity Discussion: These findings validate the broader utility of the previously identified HER2/neu-specific TCR repertoire and elucidate the molecular mechanisms driving its therapeutic efficacy, demonstrating the potential of TCR-T cells for treating solid tumors through robust cytotoxic activity and the emergence of a favorable CD4+CD8+ T cell population. This study offers critical mechanistic insights, establishing a foundation for advancing TCR-engineered therapies toward clinical use in HER2/neu-positive cancers.