2016
DOI: 10.4049/jimmunol.1600104
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Abstract: The enhanced expression of T cell Ig and mucin protein-3 (TIM-3) on tumor-associated dendritic cells (DCs) attenuates antitumor effects of DNA vaccines. To identify a potential target (or targets) for reducing TIM-3 expression on tumor-associated DCs, we explored the molecular mechanisms regulating TIM-3 expression. In this study, we have identified a novel signaling pathway (c-Src→Bruton’s tyrosine kinase→transcription factors Ets1, Ets2, USF1, and USF2) necessary for TIM-3 upregulation on DCs. Both IL-10 and… Show more

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Cited by 14 publications
(6 citation statements)
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“…In this regard, it could be argued that the anti-TIM-3 antibody might have blocked TIM-3-mediated inhibition of other cells (e.g., T cells [ 20 ]) regulating DC function and thereby indirectly improved the activation/maturation ability of sDCs in L. donovani -infected mice. Although our current findings do not rule out this possibility, TIM-3 is reported to be abundantly expressed by various DC lineages including sDCs ( 24 , 36 , 37 ). Accordingly, it is quite logical to believe that when anti-TIM-3 antibody was administered to L. donovani -infected mice, at least a fraction of this antibody was bound to TIM-3 expressed on sDCs and thereby prevented L. donovani -induced inhibition of sDCs.…”
Section: Resultscontrasting
confidence: 78%
See 1 more Smart Citation
“…In this regard, it could be argued that the anti-TIM-3 antibody might have blocked TIM-3-mediated inhibition of other cells (e.g., T cells [ 20 ]) regulating DC function and thereby indirectly improved the activation/maturation ability of sDCs in L. donovani -infected mice. Although our current findings do not rule out this possibility, TIM-3 is reported to be abundantly expressed by various DC lineages including sDCs ( 24 , 36 , 37 ). Accordingly, it is quite logical to believe that when anti-TIM-3 antibody was administered to L. donovani -infected mice, at least a fraction of this antibody was bound to TIM-3 expressed on sDCs and thereby prevented L. donovani -induced inhibition of sDCs.…”
Section: Resultscontrasting
confidence: 78%
“…Until now, only a few studies have demonstrated the role for DC-derived TIM-3 in immune regulation and that too primarily focused in the context of antitumor immunity. For example, we and others have shown that c-Src-mediated enhancement of TIM-3 expression on tumor-associated DCs attenuates antitumor immunity ( 24 , 25 ). In addition, TIM-3 has been shown to regulate the antitumor function of intratumoral CD103 + DCs ( 26 ).…”
Section: Introductionmentioning
confidence: 99%
“…Compared to other strategies proposed to target the pathologically relevant NLRP3 inflammasome/IL-1 axis—for example, the inhibitor MCC950, whose target is however unknown ( 58 ), or IL-1 blockade which only neutralizes the inflammatory potential of certain inflammasome-dependent mediators—targeting NLRP3 via BTK is highly intriguing since BTK is a well-known (if incompletely understood) molecular target with inhibitors approved or in clinical trials. In cancer immunotherapies, first results on BTK inhibition modulating DC and subsequent CD4 + T cell activation ( 43 ) or upregulation of the inhibitory receptor TIM-3 on DCs are also noteworthy ( 59 ). On the other hand, targeting BTK with ibrutinib causes significant immunosuppression associated with an increased risk of infections ( 60 ) indicating that BTK dependent innate immunity is severely impaired ( 23 ).…”
Section: Therapeutic Opportunities In Innate Immunitymentioning
confidence: 99%
“…USF2 can form a dimer that binds to the E-box on the promoter of the target genes [20]. TGF-β can promote the transcriptional activity of USF2 in inflammatory response and renal fibrosis [21,22]. USF2 can also upregulate TGF-β expression in a positive feedback and accelerate the disease process [21].…”
Section: Introductionmentioning
confidence: 99%