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Prof. Yonghui Zhang’s Group Revealed New Immune Regulation Mechanism of Mevalonate Pathway

 

In a recent issue of Cell, Zhang’ group from Tsinghua University reported that the mevalonate pathway is a druggable target for vaccine adjuvant discovery.

The mevalonate pathway is a core metabolic pathway for cholesterol biosynthesis and protein post-translational prenylation. Mevalonate pathway is an essential enzyme in the mevalonate pathway that catalyzes the phosphorylation of mevalonate. Patients carrying loss-of-function mutations of mevalonate kinase develop immune stimulatory phenotypes, such as periodic fever, increased inflammatory cytokine production and sometimes elevated serum immunoglobulin levels. This led the researchers to the hypothesis that targeting the mevalonate pathway might boost immunity.

Statins and bisphosphonates, drugs used to treat hypercholesterolemia and bone disorders respectively, target the mevalonate pathway. Using extensive medicinal chemistry, researchers gathered strong evidence that lipophilic statins and bisphosphonates are potent vaccine adjuvants, exerting their immune-regulatory functions independently of conventional danger sensing and inflammasome activation. These results indicate that the adjuvanticity is biochemically unrelated to the terminal cholesterol-lowering effects but dependent on protein prenylation that is regulated by the mevalonate pathway. Further it was demonstrated that these adjuvants inhibit the formation of the downstream metabolite geranylgeranyl diphosphate that is essential for small GTPase geranylgeranylation in antigen presenting cells, which results in arrested endosome maturation, prolonged antigen retention, enhanced antigen presentation and T cell activation.

In this research, a unique approach has been illustrated to enhance antigen immunogenicity by inhibiting the mevalonate pathway. The adjuvanticity associated with the mevalonate pathway inhibition covers multiple arms of immunity, including Th1 and cytolytic T cell responses and is thus suitable for cancer immunotherapies. This research represents one of the few examples of rational selection of a drug target from phenotype of a rare disease and presents a new approach for the development of both vaccine adjuvants and cancer immunotherapies.