Virus-Mimic mRNA Vaccine for Cancer Treatment.

Abstract

An effective therapeutic cancer vaccine should be empowered with the capacity to overcome the immunosuppressive tumor microenvironment. Here, the authors describe a mRNA virus‐mimicking vaccine platform that is comprised of a phospholipid bilayer encapsulated with a protein‐nucleotide core consisting of antigen‐encoding mRNA molecules, unmethylated CpG oligonucleotides and positively charged proteins. In cell culture, VLVP potently stimulated bone marrow‐derived dendritic cells (BMDCs) to express inflammatory cytokines that facilitated dendritic cell (DC) maturation and promoted antigen processing and presentation. In tumor‐bearing mice, VLVP treatment stimulated proliferation of antigen‐specific CD8+T cells in the lymphatic organs and T cell infiltration into the tumor bed, resulting in potent anti‐tumor immunity. Cytometry by time of flight (CyTOF) analysis revealed that VLVP treatment stimulated a 5‐fold increase in tumor‐associated CD8+DCs and a 4‐fold increase in tumorinfiltrated CD8+T cells, with concurrent decreases in tumor‐associated bone marrow‐derived suppressor cells and arginase 1‐ expressing suppressive DCs. Finally, CpG oligonucleotide is an essential adjuvant for vaccine activity. Inclusion of CpG not only maximized vaccine activity but also prevented PD‐1 expression in T cells, serving the dual roles as a potent adjuvant and a checkpoint blockade agent.