High Throughput Screening Identifies CDK Inhibitors as Inflammasome-Activating Vaccine Adjuvants
Year: 2023
Type: conference-abstract
Abstract: Several FDA-approved adjuvant formulations, such as saponins and lipid nanoparticles, have been shown to mediate their adjuvant effects in part through the NLRP3 inflammasome. These formulations are among the most potent adjuvants in use, but they are limited by poor synthetic control and immunotoxic side effects. New small molecule adjuvants targeting the NLRP3 inflammasome would allow broader implementation of subunit- and nucleotide-based vaccines against poorly immunogenic antigens. In this work, we leverage high throughput screening of immunomodulatory compounds to identify cyclin dependent kinase (CDK) inhibitors as a novel class of inflammasome-activating small molecule adjuvants. CDK inhibitors are FDA-approved anti-cancer drugs which block cell cycle progression to prevent tumor proliferation. When co-administered with a Toll-like receptor (TLR) agonist, we observe that these inhibitors induce robust NLRP3- and Caspase-dependent IL-1β secretion in primary murine and human dendritic cells. When formulated with a TLR4 agonist and ovalbumin for use in vaccination, these compounds were found to enhance antibody production and antigen-specific CD8+ T cell proliferation relative to formulation controls. While greater work is needed to formulate and optimize these adjuvants, understanding the mechanism of CDK inhibitors’ adjuvanticity will both enhance our understanding of these compounds and expand their use case to vaccination. Supported by grants from NIH (75N93019C00041, T32 GM008720) and DTRA (1-18-1-0052).
Source: The Journal of Immunology
Institution: University of Chicago
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4385686981