Mouse melanomas treated with epitope-standardized adoptive T-cell therapy targeting different endogenous gene products

Using a CRISPR-Cas9 based approach we fused a model CD8 T-cell epitope to the C-termini of different endogenous gene products. By this approach we could target different endogenous gene products with the same epitope-specific T cell receptor (TCR)-transgenic CD8+ T-cells. This epitope-standardized adoptive T-cell therapy (esACT) allowed us to directly compare how function and regulation of epitope-encoding gene products influence responsiveness and mechanisms of immune evasion. We analysed non-treated, esACT-treated (early during treatment) and esACT-treated recurrent melanomas in syngeneic mice. As proof-of-concept targets for esACT we chose melanosomal TYRP1 and oncogeneic CDk4-R24C, as the transplantable melanoma model harbors this oncogenic driver mutation. Our approachs revealed diversity of immune evasion mechanisms in melanoma in part dependent on the targeted gene product.