Exposure to ionizing radiation,a physical treatment that inactivates live tumor cells,has been extensively applied to enhance the antitumor responses induced by cancer cell vaccines in both animal research and human c...Exposure to ionizing radiation,a physical treatment that inactivates live tumor cells,has been extensively applied to enhance the antitumor responses induced by cancer cell vaccines in both animal research and human clinical trials.However,the mechanisms by which irradiated cells function as immunogenic tumor vaccines and induce effective antitumor responses have not been fully explored.Here,we demonstrate that oxidized mitochondrial DNA(mtDNA)and stimulator of interferon genes(STING)signaling play a key roles in the enhanced antitumor effect achieved with an irradiated tumor cell vaccine.Elevations in ROS and oxidized mtDNA 8-OHG content could be induced in irradiated tumor cells.Oxidized mtDNA derived from irradiated tumor cells gained access to the cytosol of dendritic cells(DCs).Oxidized mtDNA,as a DAMP or adjuvant,activated the STING-TBK1-IRF3-IFN-β pathway in DCs,which subsequently cross-presented irradiated tumor cell-derived antigens to CD8^(+)T cells and elicited antitumor immunity.The results of our study provide insight into the mechanism by which an irradiated cell vaccine mediates antitumor immunity,which may have implications for new strategies to improve the efficacy of irradiated vaccines.展开更多
Glioblastoma multiforme(GBM)is characterized by extensive endothelial hyperplasia.Recent studies suggest that a subpopulation of endothelial cells originates via vasculogenesis by the transdifferentiation of GBM tumor...Glioblastoma multiforme(GBM)is characterized by extensive endothelial hyperplasia.Recent studies suggest that a subpopulation of endothelial cells originates via vasculogenesis by the transdifferentiation of GBM tumor cells into endothelial cells(endotransdifferentiation).The molecular mechanism underlying this process remains poorly defined.Here,we show that the expression of ETS variant 2(ETV2),a master regulator of endothelial cell development,is highly correlated with malignancy.Functional studies demonstrate that ETV2 is sufficient and necessary for the transdifferentiation of a subpopulation of CD133+/Nestin+GBM/neural stem cells to an endothelial lineage.Combinational studies of ChIP-Seq with gain-of-function RNA-Seq data sets suggest that ETV2,in addition to activating vascular genes,represses proneural genes to direct endo-transdifferentiation.Since endotransdifferentiation by ETV2 is VEGF-A independent,it likely accounts for the observed resistance of GBM tumor cells to antiangiogenesis therapy.Further characterization of the regulatory networks mediated by ETV2 in endo-transdifferentiation of GBM tumor cells should lead to the identification of more effective therapeutic targets for GBM.展开更多
To the Editor:Epithelial ovarian cancer has the highest mortality rate among all gynecologic cancers.Cisplatin and carboplatin are the primary first-line therapies for the treatment of ovarian cancer.
Signal transducers and activators of transcription 5(Stat5)is known to engage in regulating the differentiation and effector function of various subsets of T helper cells.However,how Stat5 regulates the antitumor acti...Signal transducers and activators of transcription 5(Stat5)is known to engage in regulating the differentiation and effector function of various subsets of T helper cells.However,how Stat5 regulates the antitumor activity of tumor-infiltrating CD4^(+)T cells is largely unknown.Here,we showed that mice with specific deletion of Stat5 in CD4^(+)T cells were less susceptible to developing subcutaneous and lung metastatic B16 melanoma with CD4^(+)tumor-infiltrating lymphocytes(TILs)remolding.Especially,we confirmed that Stat5-deficient CD4^(+)naïve T cells were prone to polarization of two subtypes of Th17 cells:IFN-γ^(+)and IFN-γ^(-)Th17 cells,which exhibited increased anti-melanoma activity through enhanced activation of Notch1 pathway compared with wild type Th17 cells.Our study therefore revealed a novel function of Stat5 in regulating tumor-specific Th17 cell differentiation and function in melanoma.This study also provided a new possibility for targeting Stat5 and other Th17-associated pathways to develop novel immunotherapies for melanoma patients.展开更多
基金This work was supported by the National Natural Science Foundation Regional Innovation and Development(No.U19A2003)National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2018ZX09733001)+1 种基金Excellent Youth Foundation of the Sichuan Scientific Committee Grant in China(No.2019JDJQ008)Development Program of China(No.2016YFA0201402).
文摘Exposure to ionizing radiation,a physical treatment that inactivates live tumor cells,has been extensively applied to enhance the antitumor responses induced by cancer cell vaccines in both animal research and human clinical trials.However,the mechanisms by which irradiated cells function as immunogenic tumor vaccines and induce effective antitumor responses have not been fully explored.Here,we demonstrate that oxidized mitochondrial DNA(mtDNA)and stimulator of interferon genes(STING)signaling play a key roles in the enhanced antitumor effect achieved with an irradiated tumor cell vaccine.Elevations in ROS and oxidized mtDNA 8-OHG content could be induced in irradiated tumor cells.Oxidized mtDNA derived from irradiated tumor cells gained access to the cytosol of dendritic cells(DCs).Oxidized mtDNA,as a DAMP or adjuvant,activated the STING-TBK1-IRF3-IFN-β pathway in DCs,which subsequently cross-presented irradiated tumor cell-derived antigens to CD8^(+)T cells and elicited antitumor immunity.The results of our study provide insight into the mechanism by which an irradiated cell vaccine mediates antitumor immunity,which may have implications for new strategies to improve the efficacy of irradiated vaccines.
基金This work was supported by grants from the National Natural Science Foundation of China(Grant no.81402275,81502522and 81500153)+2 种基金Guangdong Innovative Research Team Program(Grand 2011Y073)China Postdoctoral Science Foundation(58-2549)CSCO-MERCK SERONO ONCOLOGY RESEARCH FUND(Y-MX2015-018).
文摘Glioblastoma multiforme(GBM)is characterized by extensive endothelial hyperplasia.Recent studies suggest that a subpopulation of endothelial cells originates via vasculogenesis by the transdifferentiation of GBM tumor cells into endothelial cells(endotransdifferentiation).The molecular mechanism underlying this process remains poorly defined.Here,we show that the expression of ETS variant 2(ETV2),a master regulator of endothelial cell development,is highly correlated with malignancy.Functional studies demonstrate that ETV2 is sufficient and necessary for the transdifferentiation of a subpopulation of CD133+/Nestin+GBM/neural stem cells to an endothelial lineage.Combinational studies of ChIP-Seq with gain-of-function RNA-Seq data sets suggest that ETV2,in addition to activating vascular genes,represses proneural genes to direct endo-transdifferentiation.Since endotransdifferentiation by ETV2 is VEGF-A independent,it likely accounts for the observed resistance of GBM tumor cells to antiangiogenesis therapy.Further characterization of the regulatory networks mediated by ETV2 in endo-transdifferentiation of GBM tumor cells should lead to the identification of more effective therapeutic targets for GBM.
基金This work was supported by,grants from the Medical Association Foundation of Sichuan Province of China(No.S19061)the Fundamental Research Funds for theCentral Universities(No.SCU2020D4132).
文摘To the Editor:Epithelial ovarian cancer has the highest mortality rate among all gynecologic cancers.Cisplatin and carboplatin are the primary first-line therapies for the treatment of ovarian cancer.
基金supported by start-up funds for Prof. Xin-Yuan Fu (139170082)sponsored by West China Hospital, Sichuan Universityin part by the Chinese National Natural Science Funds (81902947)。
文摘Signal transducers and activators of transcription 5(Stat5)is known to engage in regulating the differentiation and effector function of various subsets of T helper cells.However,how Stat5 regulates the antitumor activity of tumor-infiltrating CD4^(+)T cells is largely unknown.Here,we showed that mice with specific deletion of Stat5 in CD4^(+)T cells were less susceptible to developing subcutaneous and lung metastatic B16 melanoma with CD4^(+)tumor-infiltrating lymphocytes(TILs)remolding.Especially,we confirmed that Stat5-deficient CD4^(+)naïve T cells were prone to polarization of two subtypes of Th17 cells:IFN-γ^(+)and IFN-γ^(-)Th17 cells,which exhibited increased anti-melanoma activity through enhanced activation of Notch1 pathway compared with wild type Th17 cells.Our study therefore revealed a novel function of Stat5 in regulating tumor-specific Th17 cell differentiation and function in melanoma.This study also provided a new possibility for targeting Stat5 and other Th17-associated pathways to develop novel immunotherapies for melanoma patients.