Indirect stimulation of human Vγ2Vδ2 T cells through alterations in isoprenoid metabolism: implications for cancer immunotherapy (48.14)

Abstract Human Vγ2Vδ2 T cells monitor isoprenoid metabolism by recognizing (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), an intermediate in the foreign MEP pathway used by protozoa and bacteria, and isopentenyl pyrophosphate (IPP), an intermediate in the self mevalonate pathway. Synthetic bisphosphonates (BPH), used for cancer immunotherapy, and alkylamines indirectly stimulate Vγ2Vδ2 T cells by inhibiting self farnesyl diphosphate synthase (FDPS), thereby increasing IPP which is directly stimulatory. Here, we further characterize stimulation by these compounds, and define pathways used by new classes of compounds. Consistent with FDPS inhibition, stimulation of Vγ2Vδ2 cells by BPH and alkylamines was much more sensitive to upstream statin inhibition than stimulation by phosphoantigens or mitogens. However, the continuous presence of BPH or statins was toxic, blocking Vγ2Vδ2 T cell proliferation but not cytokine release. SiRNA downregulation of FDPS in APC increased IPP and rendered them stimulatory for Vγ2Vδ2 cells. SiRNAs downregulation of isopentenyl diphosphate isomerase functioned similarly, albeit less potently. New stimulatory compounds-mevalonate and the alcohol of HMBPP-may also stimulate indirectly, but required high statin doses for inhibition. The critical chemical feature of BPH is the amino moiety, since BPH lacking amino moieties acted as direct antigens. Thus, a variety of manipulations affecting isoprenoid metabolism lead to stimulation of Vγ2Vδ2 T cells.