The mevalonate pathway for cholesterol biosynthesis and protein prenylation has been implicated in various aspects of tumor development and progression. Certain classes of drugs, such as statins and bisphosphonates, inhibit mevalonate metabolism and therefore have also been tested as antitumor agents. This concept is strongly supported by the recent finding that mutant p53, which is present in more than half of all human cancers, can significantly upregulate mevalonate metabolism and protein prenylation in carcinoma cells. The first evidence that mevalonate pathway inhibitors may have the potential to reverse the malignant phenotype has already been obtained. Moreover, recently discovered immunomodulatory properties of statins and bisphosphonates may also contribute to their known anticancer effects. Druginduced inhibition of protein prenylation may induce sequential cellular stress responses, including the unfolded protein response and autophagy, that eventually translate into inflammasome-dependent and caspase-1-mediated activation of innate immunity. This review focuses on these novel capabilities of mevalonate pathway inhibitors to beneficially affect tumor biology and contribute to tumor immune surveillance. Clin Cancer Res; 18(13); 3524-31. Ó2012 AACR.

Whereas resting T cells, which have low metabolic requirements, use oxidative phosphorylation (OXPHOS) to maximize their generation of ATP, activated T cells, similar to tumor cells, shift metabolic activity to aerobic glycolysis, which also fuels mevalonate metabolism. Both sterol and nonsterol derivatives of mevalonate affect T cell function. The intracellular availability of sterols, which is dynamically regulated by different classes of transcription factors, represents a metabolic checkpoint that modulates T cell responses. The electron carrier ubiquinone, which is modified with an isoprenoid membrane anchor, plays a pivotal role in OXPHOS, which supports the proliferation of T cells. Isoprenylation also mediates the plasma membrane attachment of the Ras, Rho, and Rab guanosine triphosphatases, which are involved in T cell immunological synapse formation, migration, proliferation, and cytotoxic effector responses. Finally, multiple phosphorylated mevalonate derivatives can act as danger signals for innate-like γδ T cells, thus contributing to the immune surveillance of stress, pathogens, and tumors. We highlight the importance of the mevalonate pathway in the metabolic reprogramming of effector and regulatory T cells.

Bisphosphonates are mainly used for the inhibition of osteoclast-mediated bone resorption but also have been shown to induce ␥␦ T-cell activation. Using IL-2-primed cultures of CD56 ؉ peripheral blood mononuclear cells, we show here that zoledronic acid (zoledronate) could induce IFN-␥ production not only in ␥␦ T lymphocytes but, surprisingly, also in natural killer (NK) cells in a manner that depended on antigen-presenting cells, which share properties of inflammatory monocytes and dendritic cells (DCs; here referred to as DC-like cells). In the presence of ␥␦ T lymphocytes, DC-like cells were rapidly eliminated, and NK cell IFN-␥ production was silenced. Conversely, in the absence of ␥␦ T lymphocytes, DClike cells were spared, allowing NK cell IFN-␥ production to proceed. ␥␦ T cellindependent NK cell activation in response to zoledronate was because of downstream depletion of endogenous prenyl pyrophosphates and subsequent caspase-1 activation in DC-like cells, which then provide mature IL-18 and IL-1␤ for the activation of IL-2-primed NK cells. Pharmacologic inhibition of caspase-1 almost abolished IFN-␥ production in NK cells and ␥␦ T lymphocytes, indicating that caspase-1-mediated cytokine maturation is the crucial mechanism underlying innate lymphocyte activation in response to zoledronate. (Blood. 2011; 118(10):2743-2751) IntroductionThe bisphosphonates zoledronate and pamidronate are approved by the Food and Drug Administration for the treatment of metastatic bone disease of hematopoietic tumors such as multiple myeloma 1,2 and nonhematopoietic tumors such as breast 3 and prostate cancer. 4 Inhibition of farnesyl pyrophosphate synthase, an enzyme of the mevalonate pathway for cholesterol biosynthesis and protein prenylation, 5 is one important mechanism for bisphosphonate effects on bone resorption. 1,4 Inhibition of farnesyl pyrophosphate synthase leads to farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) deprivation and the subsequent failure to perform farnesylation and geranylgeranylation of small guanosine triphosphatases (GTPases) of the RAS superfamily. Inhibition of RAS signaling because of the disruption of membrane anchoring of these GTPases eventually prevents osteoclast-mediated bone resorption. 6,7 In addition to their effects on bone metabolism, bisphosphonates may have immunomodulatory effects, particularly on the innate immune system. [8][9][10][11] Evidence for the stimulation of ␥␦ T lymphocytes by bisphosphonates was obtained when expansion of ␥␦ T lymphocytes was observed in patients who had acute-phase reactions after their first treatment with pamidronate. 12 Inhibition of FPP synthase by bisphosphonates leads to the accumulation of isopentenyl pyrophosphate that can be specifically recognized by ␥␦ T lymphocytes expressing the V␦2V␥9 T-cell receptors. 13 Hematopoietic tumor cell lines such as Daudi (Burkitt lymphoma) or RPMI 8226 (myeloma) are specifically recognized and lysed by these ␥␦ T lymphocytes in vitro. 14,15 Moreover, ␥␦ T lymphocytes have recently been...

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