Tipifarnib-mediated suppression of T-bet-dependent signaling pathways

Abstract

Large granular lymphocyte (LGL) leukemia is a chronic lymphoproliferative disease in which T-bet [T-box transcription factor 21 gene (tbx21)] overexpression may play a pathogenic role. T-bet orchestrates the differentiation of mature peripheral T-cells into interferon-γ (IFN-γ) and tumor necrosis factor-α producing CD4+ T-helper type I (Th1) and CD8+ T cytotoxic cells that are necessary for antiviral responses. When IL-12 is produced by antigen–presenting cells, T-bet expression is induced, causing direct stimulation of ifng gene transcription while simultaneously acting as a transcriptional repressor of the IL4 gene, which then leads to Th1 dominance and T-helper type 2 differentiation blockade. Additionally, T-bet has been shown to regulate histone acetylation of the ifng promoter and enhancer to loosen condensed DNA, creating greater accessibility for other transcription factor binding, which further amplifies IFNγ production. We found that treatment with a farnesyltransferase inhibitor tipifarnib reduced Th1 cytokines in LGL leukemia patient T-cells and blocked T-bet protein expression and IL-12 responsiveness in T-cells from healthy donors. The mechanism of suppression was based on modulation of histone acetylation of the ifng gene, which culminated in Th1 blockade.

HIV‐infected CD4+ T Cells Use T‐bet‐dependent Pathway for Production of IL‐10 Upon Antigen Recognition

“…In addition to IL‐10, stimulation of PBMCs with Env also caused secretion of higher levels of GM‐CSF, which can in turn cause enhanced HIV replication in peripheral blood monocytes/ macrophages as had been reported earlier . Although IL‐10 blockade is desirable for enhancing T cell responses , treatment with all these 3 inhibitors caused suppression of TCR‐induced IFN‐γ production and increased Th2 type of cytokines after cyclosporin A treatment in concurrence with the findings reported previously . This may affect the CTL response adversely, which needs to be considered while planning IL‐10 suppression using inhibitors of these pathways.…”

“…Th1 cells isolated from blood samples were shown to be the predominant source of productive HIV‐1 infection in some of the previously reported studies . As tipifarnib has been reported to inhibit T‐bet‐dependent pathways , it was evaluated for its role in downstream production of IL‐10 through inhibition of T‐bet‐dependent pathway. IL‐10 expression by Env‐stimulated HIV‐infected CD4+ T cells was found to be suppressed after the inhibition of T‐bet‐dependent pathway suggesting involvement of this pathway in IL‐10 expression by HIV‐infected CD4+ T cells.…”

“…The optimum concentrations of the inhibitors to be used in the assays were determined as the minimum concentration of the inhibitors suppressing the pathways maximally. The PBMCs were treated with PD98059 (25 μ m , 50 μ m and 100 μ m ), tipifarnib (5 μ m and 10 μ m ) or cyclosporin A (2 μ m , 5 μ m and 10 μ m ) for 2 h for inhibiting pathways involving ERK, T‐bet and FoxP3, respectively . Effect of PD98059 on pERK expression was evaluated after 30 min of stimulation of PBMCs with PMA.…”

“…Effect of PD98059 on pERK expression was evaluated after 30 min of stimulation of PBMCs with PMA. As the IFN‐γ production occurs as the effect of activation of the T‐bet pathway, inhibitory dose of tipifarnib was evaluated by suppression of IFN‐γ expression after overnight stimulation of PBMCs with plate bound anti‐CD3/ anti‐CD28 antibodies . The optimum concentration of tipifarnib inhibiting IFN‐γ was also evaluated to determine its effect on T‐bet suppression after 4 h of stimulation with plate bound anti‐CD3/ anti‐CD28 antibodies.…”

Single-cell RNA sequencing reveals the tumor microenvironment and facilitates strategic choices to circumvent treatment failure in a chemorefractory bladder cancer patient

“…Despite inhibition of IGFBP7 and MDK may be a useful adjunct to co-targeting tumor cells and CAFs in patients with MyoCAF-rich tumors, few targeting agents are currently available for these molecules, which led us to focus on TME that showed immunosuppressive features. MAPK pathway inhibitors such as tipifarnib stimulate recruitment of immunosuppressive M2 TAMs, PD-L1 upregulation, induction of Treg, and suppression of anti-tumor responses of CTLs [88][89][90]. Our scRNAseq data for PDX after HRAS-targeting treatment strongly indicate the involvement of an immunosuppressive TME, such as the enrichment of M2-type TAMs and exhausted CTLs.…”