目的研究细胞程序性死亡配体-1(programmed cell death protein ligand-1,PD-L1)功能抑制调控免疫活化影响ApoE^(-/-)小鼠动脉粥样硬化发生发展的机制。方法将24只ApoE^(-/-)小鼠随机分为正常组,高脂组和高脂^(+)抗PD-L1单抗组,通过高...目的研究细胞程序性死亡配体-1(programmed cell death protein ligand-1,PD-L1)功能抑制调控免疫活化影响ApoE^(-/-)小鼠动脉粥样硬化发生发展的机制。方法将24只ApoE^(-/-)小鼠随机分为正常组,高脂组和高脂^(+)抗PD-L1单抗组,通过高胆固醇饲料喂养建立动脉粥样硬化(atherosclerosis)模型。实验动物饲养70 d后,分离各组实验动物血管(主动脉根部至腹主动脉)及肝脏组织,进行油红O染色;HE染色检测肝组织病理改变;ELISA检测血清中总胆固醇(CHO)、甘油三酯(TG)、高密度脂蛋白(HDL-c)、低密度脂蛋白(LDL-c)和炎症因子(IFN-γ、TNF-α、IL-1β)含量。流式细胞计数检测肝脏淋巴细胞(CD4^(+)、CD8^(+)、CD4^(+)IFN-γ^(+)和CD8^(+)IFN-γ^(+)T细胞)。RT-PCR检测肝脏组织IFN-γ、TNF-α、IL-1β、CD4和CD8表达。结果与高脂组比较,给予抗PD-L1单抗后促血管壁及肝脏脂质累积并上调血清及肝组织CHO、TG、LDL-c和HDL-c含量。高脂饲养条件下给予抗PD-L1单抗促血清和肝组织谷丙转氨酶(GPT)和谷草转氨酶(GOT)含量升高,但是对碱性磷酸酶(AKP)含量没有影响。高脂饲养条件下给予抗PD-L1单抗促血清和肝脏组织IFN-γ、TNF-α和IL-1β含量升高。高脂饲养条件下给予抗PD-L1单抗抑制CD4表达及促CD8表达。高脂饲养条件下给予抗PD-L1单抗促肝脏CD8^(+)T和CD8^(+)IFN-γ^(+)T细胞活化,但是对CD4^(+)IFN-γ^(+)T细胞活化没有影响。结论高脂饲养条件下给予抗PD-L1单抗通过活化肝脏CD8^(+)IFN-γ^(+)T细胞损伤肝脏功能加重动脉粥样硬化。展开更多
Objective:The expression of programmed death 1(PD-1)on CD8^(+)T cells is associated with their activation and exhaustion,while CD57 serves as a senescence marker.The impact of PD-1^(+)and CD57^(+)CD8^(+)T cells on the...Objective:The expression of programmed death 1(PD-1)on CD8^(+)T cells is associated with their activation and exhaustion,while CD57 serves as a senescence marker.The impact of PD-1^(+)and CD57^(+)CD8^(+)T cells on the prognosis of patients with advanced high-grade serous ovarian cancer(HGSOC)remain unclear.Methods:We assessed the percentages of PD-1^(+)and CD57^(+)CD8^(+)T cells in tumor-infiltrating lymphocytes(TILs,n=85)and tumor ascites lymphocytes(TALs,n=87)using flow cytometry.The optimal cutoffs for these markers in TILs and TALs were determined through the log-rank maximization method.Gene expression analysis elucidated the tumor immune microenvironment(TIME,n=36).Results:Patients with higher PD-1^(+)CD8^(+)TILs(>87.8%)exhibited longer platinum-free interval(PFI)and overall survival(OS).In contrast,those with elevated CD57^(+)CD8^(+)TALs(>28.69%)were more likely to experience chemotherapy and had lower complete remission rates,shorter PFI and OS.PD-1^(+)CD8^(+)TILs are primarily displayed an effector memory state with strong proliferative and secretory capabilities.Approximately 50%of CD57^(+)CD8^(+)TALs were terminally differentiated,exhibiting significantly impaired proliferation.Based on the proportions of PD-1^(+)CD8^(+)TILs and CD57^(+)CD8^(+)TALs,patients were categorized into good,median and poor prognosis groups,with median PFI of 47.78,27.29 and 11.96 months,respectively(P<0.0001).Median OS for these groups was not reach,49.23 and 30.92 months,respectively(P<0.0001).Patients with poor prognosis exhibit significantly reduced CD8^(+)T cell proportion and increased M2 macrophage in the TIME,alongside downregulation of multiple T cell activation-related pathways.Conclusions:Lower levels of PD-1^(+)CD8^(+)TILs and higher CD57^(+)CD8^(+)TALs,assessed prior to treatment,correlated with poor prognosis and suppressive TIME in advanced HGSOC.展开更多
Exhausted T cell(Tex)is a specific state of T cell dysfunction,in which these T cells gradually lose their effector function and change their phenotype during chronic antigen stimulation.The enrichment of exhausted CD...Exhausted T cell(Tex)is a specific state of T cell dysfunction,in which these T cells gradually lose their effector function and change their phenotype during chronic antigen stimulation.The enrichment of exhausted CD8^(+)T cell(CD8^(+)Tex)in the tumor microenvironment is one of the important reasons leading to the poor efficacy of immunotherapy.Recent studies have reported many reasons leading to the CD8^(+)T cell exhaustion.In addition to cancer cells,myeloid cells can also contribute to T cell exhaustion via many ways.In this review,we discuss the history of the concept of exhaustion,CD8^(+)T cell dysfunction states,the heterogeneity,origin,and characteristics of CD8^(+)Tex.We then focus on the effects of myeloid cells on CD8^(+)Tex,including tumor-associated macrophages(TAMs),dendritic cells(DCs)and neutrophils.Finally,we systematically summarize current strategies and recent advancements in therapies reversing and CD8^(+)T cell exhaustion.展开更多
文摘目的研究细胞程序性死亡配体-1(programmed cell death protein ligand-1,PD-L1)功能抑制调控免疫活化影响ApoE^(-/-)小鼠动脉粥样硬化发生发展的机制。方法将24只ApoE^(-/-)小鼠随机分为正常组,高脂组和高脂^(+)抗PD-L1单抗组,通过高胆固醇饲料喂养建立动脉粥样硬化(atherosclerosis)模型。实验动物饲养70 d后,分离各组实验动物血管(主动脉根部至腹主动脉)及肝脏组织,进行油红O染色;HE染色检测肝组织病理改变;ELISA检测血清中总胆固醇(CHO)、甘油三酯(TG)、高密度脂蛋白(HDL-c)、低密度脂蛋白(LDL-c)和炎症因子(IFN-γ、TNF-α、IL-1β)含量。流式细胞计数检测肝脏淋巴细胞(CD4^(+)、CD8^(+)、CD4^(+)IFN-γ^(+)和CD8^(+)IFN-γ^(+)T细胞)。RT-PCR检测肝脏组织IFN-γ、TNF-α、IL-1β、CD4和CD8表达。结果与高脂组比较,给予抗PD-L1单抗后促血管壁及肝脏脂质累积并上调血清及肝组织CHO、TG、LDL-c和HDL-c含量。高脂饲养条件下给予抗PD-L1单抗促血清和肝组织谷丙转氨酶(GPT)和谷草转氨酶(GOT)含量升高,但是对碱性磷酸酶(AKP)含量没有影响。高脂饲养条件下给予抗PD-L1单抗促血清和肝脏组织IFN-γ、TNF-α和IL-1β含量升高。高脂饲养条件下给予抗PD-L1单抗抑制CD4表达及促CD8表达。高脂饲养条件下给予抗PD-L1单抗促肝脏CD8^(+)T和CD8^(+)IFN-γ^(+)T细胞活化,但是对CD4^(+)IFN-γ^(+)T细胞活化没有影响。结论高脂饲养条件下给予抗PD-L1单抗通过活化肝脏CD8^(+)IFN-γ^(+)T细胞损伤肝脏功能加重动脉粥样硬化。
基金supported by National Natural Science Foundation of China(No.82372888)National Key Research and Development Program of China(No.2022YFC2704000)+6 种基金National Natural Science Foundation of China(No.82273383)the Capital’s Funds for Health Improvement and Research(No.2020-2-4098)Youth program of Beijing Municipal Natural Science Foundation(No.7204328)Clinical Medicine Plus X-Young Scholars Project,Peking University(No.PKU2022LCXQ020)Key Clinical Project of Peking University Third Hospital(No.BYSY2022050)Key Clinical Projects of Peking University Third Hospital(No.BYSYZD2021006)Key Clinical Projects of Peking University Third Hospital(No.BYSYZD2019034).
文摘Objective:The expression of programmed death 1(PD-1)on CD8^(+)T cells is associated with their activation and exhaustion,while CD57 serves as a senescence marker.The impact of PD-1^(+)and CD57^(+)CD8^(+)T cells on the prognosis of patients with advanced high-grade serous ovarian cancer(HGSOC)remain unclear.Methods:We assessed the percentages of PD-1^(+)and CD57^(+)CD8^(+)T cells in tumor-infiltrating lymphocytes(TILs,n=85)and tumor ascites lymphocytes(TALs,n=87)using flow cytometry.The optimal cutoffs for these markers in TILs and TALs were determined through the log-rank maximization method.Gene expression analysis elucidated the tumor immune microenvironment(TIME,n=36).Results:Patients with higher PD-1^(+)CD8^(+)TILs(>87.8%)exhibited longer platinum-free interval(PFI)and overall survival(OS).In contrast,those with elevated CD57^(+)CD8^(+)TALs(>28.69%)were more likely to experience chemotherapy and had lower complete remission rates,shorter PFI and OS.PD-1^(+)CD8^(+)TILs are primarily displayed an effector memory state with strong proliferative and secretory capabilities.Approximately 50%of CD57^(+)CD8^(+)TALs were terminally differentiated,exhibiting significantly impaired proliferation.Based on the proportions of PD-1^(+)CD8^(+)TILs and CD57^(+)CD8^(+)TALs,patients were categorized into good,median and poor prognosis groups,with median PFI of 47.78,27.29 and 11.96 months,respectively(P<0.0001).Median OS for these groups was not reach,49.23 and 30.92 months,respectively(P<0.0001).Patients with poor prognosis exhibit significantly reduced CD8^(+)T cell proportion and increased M2 macrophage in the TIME,alongside downregulation of multiple T cell activation-related pathways.Conclusions:Lower levels of PD-1^(+)CD8^(+)TILs and higher CD57^(+)CD8^(+)TALs,assessed prior to treatment,correlated with poor prognosis and suppressive TIME in advanced HGSOC.
基金supported by grants from the National Key Research and Development Program of China(No.2022YFA1304504)National Natural Science Foundation of China(No.82293633 and 82270180)。
文摘Exhausted T cell(Tex)is a specific state of T cell dysfunction,in which these T cells gradually lose their effector function and change their phenotype during chronic antigen stimulation.The enrichment of exhausted CD8^(+)T cell(CD8^(+)Tex)in the tumor microenvironment is one of the important reasons leading to the poor efficacy of immunotherapy.Recent studies have reported many reasons leading to the CD8^(+)T cell exhaustion.In addition to cancer cells,myeloid cells can also contribute to T cell exhaustion via many ways.In this review,we discuss the history of the concept of exhaustion,CD8^(+)T cell dysfunction states,the heterogeneity,origin,and characteristics of CD8^(+)Tex.We then focus on the effects of myeloid cells on CD8^(+)Tex,including tumor-associated macrophages(TAMs),dendritic cells(DCs)and neutrophils.Finally,we systematically summarize current strategies and recent advancements in therapies reversing and CD8^(+)T cell exhaustion.
