Vaccines targeting p53 mutants elicit anti-tumor immunity

Abstract

The p53 tumor suppressor is commonly mutated in cancer; however, there are no effective treatments targeting p53 mutants. A DNA vaccine gWIZ-S237G targeting the p53 S237G mutant, which is highly expressed in A20 murine tumor cells, was developed and administered intramuscularly via electroporation, either alone or in combination with PD1 blockade. The anti-p53-S237G immunization elicited a robust protective response against subcutaneous A20 tumors and facilitated the infiltration of immune cells including CD8⁺ T cells, NK cells, and DCs. The vaccine enhanced the induction and maturation of CD11c⁺, CD103⁺CD11c⁺, and CD8⁺CD11c⁺ cells, which in turn promoted tumor-specific antibody production, as well as Th1 and CD8⁺ T cell-mediated immune responses. Several antigenic epitopes of p53-S237G effectively stimulated multifunctional CD8⁺ T cells to secrete IFN-γ and TNF-α. The vaccine showed long-term anti-tumor effects that were dependent on memory CD8⁺ T cells. Furthermore, the anti-p53-S237G vaccine exhibited significant protective efficacy in the A20 liver metastasis models. When combined with PD-1 inhibition, the vaccine showed superior inhibition of tumor growth and liver metastasis. Targeting p53 mutants by vaccination represents a potential precision medicine strategy against cancers harboring p53 mutations.

Keywords: CD8(+) T cells; DNA vaccine; Mutant p53; PD1.