Somatic mutations in tumors often generate neoproteins that contain MHC-I-binding neoepitopes. Little is known if and how efficient tumor-specific neoantigens activate CD8⁺ T cells. Here, we asked whether a de novo generated neoepitope, encoded either within an otherwise conserved and ubiquitously expressed self-antigen or in a chimeric HBV core antigen expression platform, providing heterologous helper functions, induces CD8⁺ T cells in C57Bl/6J mice by DNA immunization. For it, we chose an established D^b/Sp_{244-252/R251H} neoepitope generated in the murine Endophilin-B2/SH3GLB2 (EndoB2-Sp) protein by a single amino acid exchange. We showed that a single injection of EndoB2-Sp expression vectors efficiently primed dimer/pentamer⁺, IFN-γ⁺ and cytolytic D^b/Sp_{244-252/R251H}-specific effector CD8⁺ T cells in C57Bl/6J mice. Priming of D^b/Sp_{244-252/R251H}-specific CD8⁺ T cells proceeded independent from CD4⁺ T-cell help in MHC-II-deficient Aα^-/- mice. As compared to the homologous EndoB2-Sp vaccine, the selective expression of the D^b/Sp_{244-252/R251H} neoepitope in chimeric particle-forming and assembly-deficient HBV core antigens induced comparable frequencies D^b/Sp_{244-252/R251H}-specific CD8⁺ T cells with the same cytolytic effector phenotype. The homologous EndoB2 carrier, but not the nine-residue neoepitope presented on chimeric HBV core particles, induced EndoB2-specific IgG antibody responses. The HBV core expression platform is thus an attractive option to selectively induce neoepitope-specific effector CD8⁺ T cells by DNA vaccination. These novel findings have practical implications for the design of heterologous/self and heterologous/viral cancer vaccines that prime and/or activate neoepitope-specific CD8⁺ T cells.

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