Myeloid-derived suppressor cells(MDSCs)are a main driver of immunosuppression in tumors.Understanding the mechanisms that determine the development and immunosuppressive function of these cells could provide new thera...Myeloid-derived suppressor cells(MDSCs)are a main driver of immunosuppression in tumors.Understanding the mechanisms that determine the development and immunosuppressive function of these cells could provide new therapeutic targets to improve antitumor immunity.Here,using preclinical murine models,we discovered that exportin 1(XPO1)expression is upregulated in tumor MDSCs and that this upregulation is induced by IL-6-induced STAT3 activation during MDSC differentiation.XPO1 blockade transforms MDSCs into T-cell-activating neutrophil-like cells,enhancing the antitumor immune response and restraining tumor growth.Mechanistically,XPO1 inhibition leads to the nuclear entrapment of ERK1/2,resulting in the prevention of ERK1/2 phosphorylation following the IL-6-mediated activation of the MAPK signaling pathway.Similarly,XPO1 blockade in human MDSCs induces the formation of neutrophil-like cells with immunostimulatory functions.Therefore,our findings revealed a critical role for XPO1 in MDSC differentiation and suppressive functions;exploiting these new discoveries revealed new targets for reprogramming immunosuppressive MDSCs to improve cancer therapeutic responses.展开更多
Tea domain transcription factor 4 (TEAD4) plays a pivotal role in tissue development and homeostasis by interacting with Yesassociated protein (YAP) in response to Hippo signaling inactivation. TEAD4 and YAP can also ...Tea domain transcription factor 4 (TEAD4) plays a pivotal role in tissue development and homeostasis by interacting with Yesassociated protein (YAP) in response to Hippo signaling inactivation. TEAD4 and YAP can also cooperate with transforminggrowth factor-β (TGF-β)-activated Smad proteins to regulate gene transcription. Yet, it remains unclear whether TEAD4 playsa YAP-independent role in TGF-β signaling. Here, we unveil a novel tumor suppressive function of TEAD4 in liver cancer viamitigating TGF-β signaling. Ectopic TEAD4 inhibited TGF-β-induced signal transduction, Smad transcriptional activity, and targetgene transcription, consequently suppressing hepatocellular carcinoma cell proliferation and migration in vitro and xenografttumorgrowth in mice. Consistently, depletion of endogenous TEAD4 by siRNAs enhanced TGF-β signaling in cancer cells. Mechanistically,TEAD4 associates with receptor-regulated Smads (Smad2/3) and Smad4 in the nucleus, thereby impairing the binding of Smad2/3to the histone acetyltransferase p300. Intriguingly, these negative effects of TEAD4 on TGF-β/Smad signaling are independent ofYAP, as impairing the TEAD4–YAP interaction through point mutagenesis or depletion of YAP and/or its paralog TAZ has little effect.Together, these results unravel a novel function of TEAD4 in fine tuning TGF-β signaling and liver cancer progression in a YAPindependent manner.展开更多
基金National Institutes of Health,National Heart Lung Blood Institute(K99 HL155792,R00HL155792 to HM)Roswell Park Alliance(HM),a gift from Brendan and Elise McCarthy(PLM),and R01 CA205246(ER)+1 种基金Cytometry services were provided by the Flow and Image Cytometry Shared Resource at the Roswell Park Comprehensive Cancer Center,which is supported in part by the NCI Cancer Center Support Grant NCI R50CA211108NCI grant P30CA016056 involving the use of Roswell Park Comprehensive Cancer Center’s Genomic and Flow and Image Cytometry Shared Resources.Selinexor was provided by Karyopharm,Newton,MA.
文摘Myeloid-derived suppressor cells(MDSCs)are a main driver of immunosuppression in tumors.Understanding the mechanisms that determine the development and immunosuppressive function of these cells could provide new therapeutic targets to improve antitumor immunity.Here,using preclinical murine models,we discovered that exportin 1(XPO1)expression is upregulated in tumor MDSCs and that this upregulation is induced by IL-6-induced STAT3 activation during MDSC differentiation.XPO1 blockade transforms MDSCs into T-cell-activating neutrophil-like cells,enhancing the antitumor immune response and restraining tumor growth.Mechanistically,XPO1 inhibition leads to the nuclear entrapment of ERK1/2,resulting in the prevention of ERK1/2 phosphorylation following the IL-6-mediated activation of the MAPK signaling pathway.Similarly,XPO1 blockade in human MDSCs induces the formation of neutrophil-like cells with immunostimulatory functions.Therefore,our findings revealed a critical role for XPO1 in MDSC differentiation and suppressive functions;exploiting these new discoveries revealed new targets for reprogramming immunosuppressive MDSCs to improve cancer therapeutic responses.
基金supported by grants from the NationalNatural Science Foundation of China(NSFC32060148,31871378,82172888,and 81860546)+2 种基金the Natural Science Foundation of Jiangxi Province of China(20224ACB206032)the Talent Plan of Jiangxi Province of China(jxsq2018106037)the Jiangxi Province Graduate Innovation Fund(YC2018-B017).
文摘Tea domain transcription factor 4 (TEAD4) plays a pivotal role in tissue development and homeostasis by interacting with Yesassociated protein (YAP) in response to Hippo signaling inactivation. TEAD4 and YAP can also cooperate with transforminggrowth factor-β (TGF-β)-activated Smad proteins to regulate gene transcription. Yet, it remains unclear whether TEAD4 playsa YAP-independent role in TGF-β signaling. Here, we unveil a novel tumor suppressive function of TEAD4 in liver cancer viamitigating TGF-β signaling. Ectopic TEAD4 inhibited TGF-β-induced signal transduction, Smad transcriptional activity, and targetgene transcription, consequently suppressing hepatocellular carcinoma cell proliferation and migration in vitro and xenografttumorgrowth in mice. Consistently, depletion of endogenous TEAD4 by siRNAs enhanced TGF-β signaling in cancer cells. Mechanistically,TEAD4 associates with receptor-regulated Smads (Smad2/3) and Smad4 in the nucleus, thereby impairing the binding of Smad2/3to the histone acetyltransferase p300. Intriguingly, these negative effects of TEAD4 on TGF-β/Smad signaling are independent ofYAP, as impairing the TEAD4–YAP interaction through point mutagenesis or depletion of YAP and/or its paralog TAZ has little effect.Together, these results unravel a novel function of TEAD4 in fine tuning TGF-β signaling and liver cancer progression in a YAPindependent manner.
