The Mevalonate Pathway Is a Druggable Target for Vaccine Adjuvant Discovery

• Published in: Cell Vol. 175; no. 4; pp. 1059 - 1073.e21
• Main Authors: Xia, Yun, Xie, Yonghua, Yu, Zhengsen, Xiao, Hongying, Jiang, Guimei, Zhou, Xiaoying, Yang, Yunyun, Li, Xin, Zhao, Meng, Li, Liping, Zheng, Mingke, Han, Shuai, Zong, Zhaoyun, Meng, Xianbin, Deng, Haiteng, Ye, Huahu, Fa, Yunzhi, Wu, Haitao, Oldfield, Eric, Hu, Xiaoyu, Liu, Wanli, Shi, Yan, Zhang, Yonghui
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2018
• Subjects: Adjuvants, Immunologic - pharmacology; Animals; Antigen Presentation; Antigen-Presenting Cells - drug effects; Antigen-Presenting Cells - immunology; bisphosphonate; cancer vaccination; Cancer Vaccines - immunology; Cell Line, Tumor; Diphosphonates - pharmacology; Endosomes - drug effects; Female; geranylgeranylation; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Macaca fascicularis; Male; mevalonate pathway; Mevalonic Acid - metabolism; Mice; Mice, Inbred C57BL; Protein Prenylation; rab5 GTP-Binding Proteins - antagonists & inhibitors; rab5 GTP-Binding Proteins - metabolism; statin; vaccine adjuvant; bisphosphonate; vaccine adjuvant; cancer vaccination; mevalonate pathway; statin; geranylgeranylation
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2018.08.070

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. [Display omitted] •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 Lipophilic statins and bisphosphonates that target three enzymes in the mevalonate pathway have vaccine adjuvant activities in mice and monkeys and can synergize with anti-PD1 therapy.