Figure 3.

NB tumor microenvironment perturbation by the combined treatment with ZOL and human Vγ9Vδ2 T cells. Inhibiting FPPS, ZOL treatment induces intracellular accumulation of upstream metabolites of the MVA pathway including IPP, which attracts and activates Vγ9Vδ2 T cells. Through perforin release and IFN-γ secretion Vγ9Vδ2 T cells may be involved in NB cell killing, inhibition of NB cell proliferation, and/or induction of apoptosis. Vγ9Vδ2 T cell-secreted IFN-γ can upregulate HLA class I expression on NB cells thus increasing their immunogenicity, and induce CXCL10 expression in tumor cells. CXCL10 may exert anti-angiogenic effects by binding to CXCR3 on endothelial cells and recruit a new wave of CXCR3⁺ Vγ9Vδ2 T cells to the tumor site. FPPS, farnesyl pyrophosphate synthase; IPP, isopentenyl pyrophosphate; MVA, mevalonate; EC, endothelial cells.