Granulocyte colony-stimulating factor （G-CSF） is an essential regulator of neutrophil trafficking and is highly expressed in multiple tumors. Myeloid derived suppressor cells （MDSCs） promote neoplastic progression...Granulocyte colony-stimulating factor （G-CSF） is an essential regulator of neutrophil trafficking and is highly expressed in multiple tumors. Myeloid derived suppressor cells （MDSCs） promote neoplastic progression through multiple mechanisms by immune suppression. Despite the findings of G-CSF function in colon cancer progression, the precise mechanism of G-CSF on MDSCs regulation and its blockade effects on tumor growth remains a worthy area of investigation. In this study we observed an overexpression of G-CSF in a mouse colitis-associated cancer （CAC） model, which was consistent with the accumulation of MDSCs in mouse colon tissues. Further in vitro studies demonstrated that G-CSF could promote MDSCs survival and activation through signal transducer and activator of transcription 3 （STAT3） signaling pathway. Moreover, compared with isotype control, anti-G-CSF mAb treatment demonstrated reduced MDSC accumulation, which led to a marked decrease in neoplasm size and number in mice. Our results indicated that G-CSF is a critical regulating molecule in the migration, proliferation and function maintenance of MDSCs, which could be a potential therapeutic target for cancer.展开更多
目的:通过研究扶正(益气养阴方)、祛邪(清热解毒方)、扶正祛邪(益气养阴解毒方)三种治则对非小细胞肺癌患者调节性T细胞(Regulatory T cell,Treg)、髓源抑制细胞(Myeloid-derived suppressor cells,MDSC)免疫指标的作用,探究不同治则对...目的:通过研究扶正(益气养阴方)、祛邪(清热解毒方)、扶正祛邪(益气养阴解毒方)三种治则对非小细胞肺癌患者调节性T细胞(Regulatory T cell,Treg)、髓源抑制细胞(Myeloid-derived suppressor cells,MDSC)免疫指标的作用,探究不同治则对非小细胞肺癌患者的免疫功能的影响。方法:采用完全随机、平行对照的实验设计,将166例非小细胞肺癌患者按照随机数字表纳入研究,完成益气养阴方组(A组)39例、清热解毒方组(B组)46例、益气养阴解毒方组(C组)49例,分别给予相应的中药汤剂,4周为一个疗程,治疗3个疗程(12周)后观察对Treg和MDSC的影响。结果:治疗前非小细胞肺癌患者外周血Treg、MDSC水平明显高于健康人群组,具有统计学意义(P<0.001)。治疗后,B组和C组能够显著降低肺癌患者的Treg、MDSC,改善机体免疫功能(P<0.05)。治疗后,A组对非小细胞肺癌患者外周血Treg、MDSC无显著调节作用(P>0.05)。治疗后,三组之间比较,B组对降低非小细胞肺癌患者的Treg、MDSC水平更有优势。结论:祛邪和扶正祛邪治则均可调控肺癌患者的免疫功能,而祛邪治则在抑制MDSC和Treg方面作用更强。展开更多
The mechanism underlying T cell-mediated fulminant hepatitis is not fully understood. In this study, we investigated whether myeloid derived suppressor cells （MDSCs） could prevent the concanavalin A （ConA）- induce...The mechanism underlying T cell-mediated fulminant hepatitis is not fully understood. In this study, we investigated whether myeloid derived suppressor cells （MDSCs） could prevent the concanavalin A （ConA）- induced hepatitis through suppressing T cell proliferation. We observed an increase in the frequencies of MDSCs in mouse spleen and liver at early stage of ConA treatment, implicating that the MDSCs might be involved in the initial resistance of mice against ConA- mediated inflammation. Subpopulation analysis showed that the MDSCs in liver of ConA-induced mice were mainly granulocytic MDSCs. Adoptive transfer of the bone marrow-derived MDSCs into ConA-treated mice showed that the MDSCs migrated into the liver and spleen where they suppressed T cell proliferation through ROS pathway. In addition, the frequencies of MDSCs in mice were also significantly increased by the treatment with immune suppressor glucocorticoids. Transfer of MDSCs into the regulatory T cell （Treg）- depleted mice showed that the protective effect of MDSCs on ConA-induced hepatitis is Treg-independent. In conclusion, our results demonstrate that MDSCs possess a direct protective role in T cell-mediated hepatitis, and increasing the frequency of MDSCs by either adoptive transfer or glucocorticoid treatment represents a potential cell-based therapeutic strategy for the acute inflammatory disease.展开更多
Myeloid derived suppressor cells(MDSC) are a heterogeneous population of immune cells that are potent suppressors of immune responses. MDSC emerge in various compartments in the body, such as blood, bonemarrow or sple...Myeloid derived suppressor cells(MDSC) are a heterogeneous population of immune cells that are potent suppressors of immune responses. MDSC emerge in various compartments in the body, such as blood, bonemarrow or spleen, especially in conditions of cancer, infections or inflammation. MDSC usually express CD11 b, CD33, and low levels of human leukocyte antigen-DR in humans or CD11 b and Gr1(Ly6C/G) in mice, and they can be further divided into granulocytic or monocytic MDSC. The liver is an important organ for MDSC induction and accumulation in hepatic as well as extrahepatic diseases. Different hepatic cells, especially hepatic stellate cells, as well as liver-derived soluble factors, including hepatocyte growth factor and acute phase proteins(SAA, KC), can promote the differentiation of MDSC from myeloid cells. Importantly, hepatic myeloid cells like neutrophils, monocytes and macrophages fulfill essential roles in acute and chronic liver diseases. Recent data from patients with liver diseases and animal models linked MDSC to the pathogenesis of hepatic inflammation, fibrosis and hepatocellular carcinoma(HCC). In settings of acute hepatitis, MDSC can limit immunogenic T cell responses and subsequent tissue injury. In patients with chronic hepatitis C, MDSC increase and may favor viral persistence. Animal models of chronic liver injury, however, have not yet conclusively clarified the involvement of MDSC for hepatic fibrosis. In human HCC and mouse models of liver cancer, MDSC are induced in the tumor environment and suppress anti-tumoral immune responses. Thus, the liver is a primary site of MDSC in vivo, and modulating MDSC functionality might represent a promising novel therapeutic target for liver diseases.展开更多
基金We thank all study participants for their contributions to this project. This work was supported by the National Basic Research Program （973 Program） （No. 2014CB542103）, Beijing Natural Science Foundation of China （Grant no.7144237）, The Beijing Training Project for The Leading Talents （Z131107000513001）, Beijing Nova Program （Z131107000413066） and the National Natural Science Foundation of China （Grant No. 81541154）.
文摘Granulocyte colony-stimulating factor （G-CSF） is an essential regulator of neutrophil trafficking and is highly expressed in multiple tumors. Myeloid derived suppressor cells （MDSCs） promote neoplastic progression through multiple mechanisms by immune suppression. Despite the findings of G-CSF function in colon cancer progression, the precise mechanism of G-CSF on MDSCs regulation and its blockade effects on tumor growth remains a worthy area of investigation. In this study we observed an overexpression of G-CSF in a mouse colitis-associated cancer （CAC） model, which was consistent with the accumulation of MDSCs in mouse colon tissues. Further in vitro studies demonstrated that G-CSF could promote MDSCs survival and activation through signal transducer and activator of transcription 3 （STAT3） signaling pathway. Moreover, compared with isotype control, anti-G-CSF mAb treatment demonstrated reduced MDSC accumulation, which led to a marked decrease in neoplasm size and number in mice. Our results indicated that G-CSF is a critical regulating molecule in the migration, proliferation and function maintenance of MDSCs, which could be a potential therapeutic target for cancer.
文摘目的:通过研究扶正(益气养阴方)、祛邪(清热解毒方)、扶正祛邪(益气养阴解毒方)三种治则对非小细胞肺癌患者调节性T细胞(Regulatory T cell,Treg)、髓源抑制细胞(Myeloid-derived suppressor cells,MDSC)免疫指标的作用,探究不同治则对非小细胞肺癌患者的免疫功能的影响。方法:采用完全随机、平行对照的实验设计,将166例非小细胞肺癌患者按照随机数字表纳入研究,完成益气养阴方组(A组)39例、清热解毒方组(B组)46例、益气养阴解毒方组(C组)49例,分别给予相应的中药汤剂,4周为一个疗程,治疗3个疗程(12周)后观察对Treg和MDSC的影响。结果:治疗前非小细胞肺癌患者外周血Treg、MDSC水平明显高于健康人群组,具有统计学意义(P<0.001)。治疗后,B组和C组能够显著降低肺癌患者的Treg、MDSC,改善机体免疫功能(P<0.05)。治疗后,A组对非小细胞肺癌患者外周血Treg、MDSC无显著调节作用(P>0.05)。治疗后,三组之间比较,B组对降低非小细胞肺癌患者的Treg、MDSC水平更有优势。结论:祛邪和扶正祛邪治则均可调控肺癌患者的免疫功能,而祛邪治则在抑制MDSC和Treg方面作用更强。
基金ACKNOWLEDGEMENTS This work was supported by grants from the National Basic Research Program （973 Program） （Nos. 2012CB517603 and 2011CB504803）, the National Natural Science Foundation of China （Grant No. 31301061）, the Natural Science Foundation of Jiangsu Province （No. BK2011013 and BK20130564）, and the Specialized Research Fund for the Doctoral Program of Higher Education （20130091120037）.
文摘The mechanism underlying T cell-mediated fulminant hepatitis is not fully understood. In this study, we investigated whether myeloid derived suppressor cells （MDSCs） could prevent the concanavalin A （ConA）- induced hepatitis through suppressing T cell proliferation. We observed an increase in the frequencies of MDSCs in mouse spleen and liver at early stage of ConA treatment, implicating that the MDSCs might be involved in the initial resistance of mice against ConA- mediated inflammation. Subpopulation analysis showed that the MDSCs in liver of ConA-induced mice were mainly granulocytic MDSCs. Adoptive transfer of the bone marrow-derived MDSCs into ConA-treated mice showed that the MDSCs migrated into the liver and spleen where they suppressed T cell proliferation through ROS pathway. In addition, the frequencies of MDSCs in mice were also significantly increased by the treatment with immune suppressor glucocorticoids. Transfer of MDSCs into the regulatory T cell （Treg）- depleted mice showed that the protective effect of MDSCs on ConA-induced hepatitis is Treg-independent. In conclusion, our results demonstrate that MDSCs possess a direct protective role in T cell-mediated hepatitis, and increasing the frequency of MDSCs by either adoptive transfer or glucocorticoid treatment represents a potential cell-based therapeutic strategy for the acute inflammatory disease.
基金Supported by The German Research Foundation(DFG Ta434/3-1 and SFB/TRR57)by the Interdisciplinary Center for Clinical Research(IZKF)Aachen
文摘Myeloid derived suppressor cells(MDSC) are a heterogeneous population of immune cells that are potent suppressors of immune responses. MDSC emerge in various compartments in the body, such as blood, bonemarrow or spleen, especially in conditions of cancer, infections or inflammation. MDSC usually express CD11 b, CD33, and low levels of human leukocyte antigen-DR in humans or CD11 b and Gr1(Ly6C/G) in mice, and they can be further divided into granulocytic or monocytic MDSC. The liver is an important organ for MDSC induction and accumulation in hepatic as well as extrahepatic diseases. Different hepatic cells, especially hepatic stellate cells, as well as liver-derived soluble factors, including hepatocyte growth factor and acute phase proteins(SAA, KC), can promote the differentiation of MDSC from myeloid cells. Importantly, hepatic myeloid cells like neutrophils, monocytes and macrophages fulfill essential roles in acute and chronic liver diseases. Recent data from patients with liver diseases and animal models linked MDSC to the pathogenesis of hepatic inflammation, fibrosis and hepatocellular carcinoma(HCC). In settings of acute hepatitis, MDSC can limit immunogenic T cell responses and subsequent tissue injury. In patients with chronic hepatitis C, MDSC increase and may favor viral persistence. Animal models of chronic liver injury, however, have not yet conclusively clarified the involvement of MDSC for hepatic fibrosis. In human HCC and mouse models of liver cancer, MDSC are induced in the tumor environment and suppress anti-tumoral immune responses. Thus, the liver is a primary site of MDSC in vivo, and modulating MDSC functionality might represent a promising novel therapeutic target for liver diseases.
