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Cell. 2018 Nov 1;175(4):1059-1073.e21. doi: 10.1016/j.cell.2018.08.070. Epub 2018 Sep 27.

The Mevalonate Pathway Is a Druggable Target for Vaccine Adjuvant Discovery.

Author information

1
School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, 100084 Beijing, China; Joint Graduate Program of Peking-Tsinghua-NIBS, School of Life Sciences, Tsinghua University, 100084 Beijing, China.
2
School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, 100084 Beijing, China.
3
School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, 100084 Beijing, China; Joint Graduate Program of Peking-Tsinghua-NIBS, School of Life Sciences, Tsinghua University, 100084 Beijing, China; Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041 Sichuan, China.
4
School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, 100084 Beijing, China; Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041 Sichuan, China.
5
Joint Graduate Program of Peking-Tsinghua-NIBS, School of Life Sciences, Tsinghua University, 100084 Beijing, China; MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, 100084 Beijing, China.
6
Institute for Immunology and School of Medicine, Tsinghua University, 100084 Beijing, China.
7
MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, 100084 Beijing, China.
8
Laboratory Animal Center, Academy of Military Medical Sciences, 100071 Beijing, China.
9
Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Academy of Military Medical Sciences, 100850 Beijing, China.
10
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
11
Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041 Sichuan, China; Institute for Immunology and School of Medicine, Tsinghua University, 100084 Beijing, China.
12
MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, 100084 Beijing, China; Institute for Immunology and School of Medicine, Tsinghua University, 100084 Beijing, China. Electronic address: liuwanli@biomed.tsinghua.edu.cn.
13
Institute for Immunology and School of Medicine, Tsinghua University, 100084 Beijing, China; Institute Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute, University of Calgary, Calgary, AB, Canada. Electronic address: yanshi@biomed.tsinghua.edu.cn.
14
School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, 100084 Beijing, China; Joint Graduate Program of Peking-Tsinghua-NIBS, School of Life Sciences, Tsinghua University, 100084 Beijing, China; Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041 Sichuan, China. Electronic address: zhangyonghui@tsinghua.edu.cn.

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.

KEYWORDS:

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

PMID:
30270039
DOI:
10.1016/j.cell.2018.08.070

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