High Throughput Screening Identifies CDK Inhibitors as Inflammasome-Activating Vaccine Adjuvants

Abstract Several FDA-approved adjuvant formulations, such as saponins and lipid nanoparticles, have been shown to mediate their effects in part through the NLRP3 inflammasome. These formulations are among most potent adjuvants use, but they limited by poor synthetic control immunotoxic side effects. New small molecule targeting inflammasome would allow broader implementation of subunit- nucleotide-based vaccines against poorly immunogenic antigens. In this work, we leverage high throughput screening immunomodulatory compounds identify cyclin dependent kinase (CDK) inhibitors a novel class inflammasome-activating adjuvants. CDK anti-cancer drugs which block cell cycle progression prevent tumor proliferation. When co-administered with Toll-like receptor (TLR) agonist, observe that these induce robust NLRP3- Caspase-dependent IL-1β secretion primary murine human dendritic cells. formulated TLR4 agonist ovalbumin for use vaccination, were found enhance antibody production antigen-specific CD8 +T proliferation relative formulation controls. While greater work is needed formulate optimize adjuvants, understanding mechanism inhibitors’ adjuvanticity will both our expand case vaccination. Supported grants from NIH (75N93019C00041, T32 GM008720) DTRA (1-18-1-0052).