Mevalonate Pathway Inhibitors May Be Effective Cancer Vaccine Adjuvants

Adjuvants are essential in the development of cancer vaccines, as these nonantigenic molecules modify the immune response to enhance efficacy, but currently only four adjuvants are FDA approved. The mevalonate pathway is a metabolic pathway involved in cholesterol biosynthesis and protein post-translational prenylation, and its disruption has been shown to stimulate immune responses, prompting Xia, Xie, Yu, and colleagues to investigate the mevalonate pathway as a druggable target in vaccine adjuvant discovery. Statins inhibit the HMG-CoA reductase, an early enzyme in the mevalonate pathway, and lipophilic statins served as potent adjuvants in mice, inducing adaptive immunity. Further, multiple inhibitors of components of the mevalonate pathway downstream of HMG-CoA reductase, such as simvastatin and lipophilic bisphosphonates, also served as vaccine adjuvants. Simvastatin increased antigen presentation by prolonging antigen preservation during endocytosis, increasing the surface availability of antigenic epitopes to confer adjuvanticity. Mechanistically, simvastatin blocked formation of the downstream mevalonate pathway metabolite geranylgeranyl diphosphate (GGPP). GGPP is required for geranylgeranylation of the small GTPase RAB5 in antigen-presenting cells. Thus, simvastatin blocked the geranylgeranylation of RAB5 to impair endosomal maturation and trafficking, thereby prolonging antigen retention. Simvastatin produced a strong Th1 and cytotoxic T-cell response in mice and enhanced the response to therapeutic cancer vaccination. Further, mevalonate pathway inhibition synergized with PD-1 blockade to further suppress tumor growth. Taken together, these findings suggest that mevalonate pathway inhibitors may serve as effective adjuvants to improve the efficacy of cancer vaccines and immunotherapy and warrant further clinical investigation.

Xia Y, Xie Y, Yu Z, Xiao H, Jiang G, Zhou X, et al. The mevalonate pathway is a druggable target for vaccine adjuvant discovery. Cell 2018 Sep 27 [Epub ahead of print].

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