A tumor-specific neoepitope expressed in homologous/self or heterologous/viral antigens induced comparable effector CD8+ T-cell responses by DNA vaccination

Abstract

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 Db/Sp244-252/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 Db/Sp244-252/R251H-specific effector CD8+ T cells in C57Bl/6J mice. Priming of Db/Sp244-252/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 Db/Sp244-252/R251H neoepitope in chimeric particle-forming and assembly-deficient HBV core antigens induced comparable frequencies Db/Sp244-252/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.