Engineering cancer cell membranes with endogenously upregulated HSP70 as a reinforced antigenic repertoire for the construction of material-free prophylactic cancer vaccines

Abstract

Immune cells distinguish cancer cells mainly relying on their membrane-membrane communication. The major challenge of cancer vaccines exists in difficult identification of cancer neoantigens and poor understanding over immune recognition mechanisms against cancer cells, particularly the combination among multiple antigens and the cooperation between antigens and immune-associated proteins. We exploit cancer cell membranes as the whole cancer antigen repertoire and reinforce its immunogenicity by cellular engineering to modulate the cytomembrane's immune-associated functions. This study reports a vaccine platform based on radiation-engineered cancer cells, of which the membrane HSP70 protein as the immune chaperon/traitor is endogenously upregulated. The resulting positive influences are shown to cover immunogenic steps occurring in antigen-presenting cells, including the uptake and the cross-presentation of the cancer antigens, thus amplifying cancer-specific immunogenicity. Membrane vaccines offer chances to introduce desired metal ions through membrane-metal complexation. Using Mn²⁺ ion as the costimulatory interferon genes agonist, immune activity is enhanced to further boost adaptive cancer immunogenicity. Results have evidenced that this artificially engineered membrane vaccine with favorable bio-safety could considerably reduce tumorigenicity and inhibit tumor growth. This study provides a universally applicable and facilely available cancer vaccine platform by artificial engineering of cancer cells to inherit and amplify the natural merits of cancer cell membranes. STATEMENT OF SIGNIFICANCE: The major challenge of cancer vaccines exists in difficult identification of cancer neoantigens and poor understanding over immune recognition mechanisms against cancer cells, particularly the combination among multiple antigens and the cooperation between antigens and immune-associated proteins. Cancer cell membrane presents superior advantages as the whole cancer antigen repertoire, including the reported and the unidentified antigens, but its immunogenicity is far from satisfactory. Cellular engineering approaches offer chances to endogenously modulate the immune-associated functions of cell membranes. Such a reinforced vaccine based on the engineered cancer cell membranes matches better the natural immune recognition pathway than the conventional vaccines.

Keywords: Antigenic repertoire; Cancer cell membrane; Cancer prophylactic vaccine; Heat shock protein 70 (HSP70); Immune recognition.