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School of Pharmaceutical Sciences

Yonghui ZHANG publishes "The mevalonate pathway is a druggable target for vaccine adjuvant discovery" in Cell

Sep 28, 2018
Highlights
Lipophilic statins and lipophilic bisphosphonates are potent vaccine adjuvants
Modulation of post-translational protein prenylation confers adjuvanticity
Decreased protein prenylation augments antigen preservation and presentation
Statin- or bisphosphonate-mediated vaccination synergizes with anti-PD1 against cancer
Summary
Motivated by the clinical observation that interruption of the mevalonate pathway stimulates immune responses, we hypothesized that this pathway may function as a druggable target for vaccine adjuvant discovery. We found that lipophilic statin drugs and rationally designed bisphosphonates that target three distinct enzymes in the mevalonate pathway have potent adjuvant activities in mice and cynomolgus monkeys. These inhibitors function independently of conventional “danger sensing.” Instead, they inhibit the geranylgeranylation of small GTPases, including Rab5 in antigen-presenting cells, resulting in arrested endosomal maturation, prolonged antigen retention, enhanced antigen presentation, and T cell activation. Additionally, inhibiting the mevalonate pathway enhances antigen-specific anti-tumor immunity, inducing both Th1 and cytolytic T cell responses. As demonstrated in multiple mouse cancer models, the mevalonate pathway inhibitors are robust for cancer vaccinations and synergize with anti-PD-1 antibodies. Our research thus defines the mevalonate pathway as a druggable target for vaccine adjuvants and cancer immunotherapies.