The Mevalonate Pathway Is a Druggable Target for Vaccine Adjuvant Discovery

Yun Xia, Yonghua Xie, Zhengsen Yu, Hongying Xiao, Guimei Jiang, Xiaoying Zhou, Yunyun Yang, Xin Li, Meng Zhao, Liping Li, Mingke Zheng, Shuai Han, Zhaoyun Zong, Xianbin Meng, Haiteng Deng, Huahu Ye, Yunzhi Fa, Haitao Wu, Eric Oldfield, Xiaoyu HuWanli Liu, Yan Shi, Yonghui Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

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. 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.

Original languageEnglish (US)
Pages (from-to)1059-1073.e21
JournalCell
Volume175
Issue number4
DOIs
StatePublished - Nov 1 2018

Keywords

  • bisphosphonate
  • cancer vaccination
  • geranylgeranylation
  • mevalonate pathway
  • statin
  • vaccine adjuvant

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'The Mevalonate Pathway Is a Druggable Target for Vaccine Adjuvant Discovery'. Together they form a unique fingerprint.

Cite this