NYESO-1 is a highly immunogenic tumour antigen found in many cancers including prostate cancer and expressed primarily in germline cells. The humanised mouse system is a powerful tool to study immunotherapies to treat human cancers. Neonatal mice given a sub lethal dose of radiation followed by intrahepatic injection of human CD34⁺ stem cells results in engraftment of differentiated human haematopoietic lineage cells in adult mice. By transducing CD34+ stem cells prior to engraftment of mice antigen-specific T-cell receptors (TCR) are introduced into humanised mice, altering the T-cell repertoire and providing a precursor population of antigen-specific T-cells. We produced lentivirus with a transgene recombinant for NYESO-1 TCR specific to the HLA-A2 “SLL” epitope peptide. In our model we targeted NYESO-1 cancer testis antigen by transducing CD34+ stem cells with NYESO-1 TCR lentivirus. We demonstrate that engraftment of mice with NYESO-1 TCR lentivirus-transduced CD34+ stem cells endowed humanised mice with a CD8+ T-cell population specific for SLL peptide antigen by flow cytometry and dextramer staining. Furthermore, splenocytes of mice expressing NYESO-1-specific TCR secreted IFN-γ in response to culture with SLL peptide, demonstrating SLL-specific peptide reactivity.

This study demonstrates the ability to introduce antigen-specific TCR into our humanised mouse model, resulting in antigen-specific CD8 T-cells able to generate a functional Th-1 immune response, thus creating a powerful tool to study vaccines for use as immunotherapies to treat cancer. Future immunological studies are underway testing vaccine strategies targeting CD141⁺ dendritic cells.