Objectives Chronic lymphocytic leukemia(CLL)is characterized by progressive immune dysregulation.Invariant natural killer T(iNKT)cells support immune surveillance,but the clinical relevance of their regulatory subsets...Objectives Chronic lymphocytic leukemia(CLL)is characterized by progressive immune dysregulation.Invariant natural killer T(iNKT)cells support immune surveillance,but the clinical relevance of their regulatory subsets remains unclear.FoxP3+regulatory iNKT cells(iNKTreg)and E4BP4+IL-10+(iNKT10)cells may reflect immunoregulatory changes associated with disease progression.The study aimed to quantify circulating iNKTreg and iNKT10 subsets and monocytic myeloid-derived suppressor cells(M-MDSCs)in treatment-naïve CLL patients and evaluate their associations with disease characteristics and time to first treatment(TTFT).Methods Peripheral blood samples from 60 untreated CLL patients and 20 healthy donors were analyzed by flow cytometry to determine iNKTreg and iNKT10 percentages,as well as indoleamine 2,3-dioxygenase(IDO)-expressing M-MDSCs.Receiver operating characteristic(ROC)curves and Cox proportional hazards models were used to assess prognostic significance.Results iNKTreg and iNKT10 percentages were significantly increased in CLL compared with healthy donors(p=0.002).Elevated iNKTreg frequencies were associated with zeta-chain-associated protein of 70 kD(ZAP-70)positivity(p=0.017),CD38 positivity(p=0.048),and treatment requirement during follow-up(p=0.016).Based on an ROC-derived cut-off of 9.6%(AUC=0.753),patients with iNKTreg≥9.6%had shorter TTFT(hazard ratio[HR]=2.71;95%confidence interval[CI],1.13–6.49;p=0.025),although the association was not retained in multivariate analysis(HR=1.27;95%CI,0.44–3.64;p=0.626).iNKTreg and iNKT10 percentages correlated positively with IDO+M-MDSCs(p=0.035 and p=0.044),but not with arginase-1(ARG1)or inducible nitric oxide synthase(NOS2).Conclusion Elevated iNKTreg levels reflect a more aggressive disease phenotype and associate with shorter TTFT in univariate analysis,supporting their exploration as complementary immunological biomarkers in CLL.Functional studies and validation in larger cohorts are needed to determine their prognostic and biological significance.展开更多
[目的]探讨西黄丸对三阴性乳腺癌肺转移的机制。[方法]构建三阴性乳腺癌4T1-BALB/c原位荷瘤小鼠,流式细胞术检测荷瘤小鼠血液、骨髓、肺组织内骨髓源性抑制细胞(MDSCs);通过苏木精-伊红(HE)染色确定小鼠肺转移微环境形成时间;利用蛋白...[目的]探讨西黄丸对三阴性乳腺癌肺转移的机制。[方法]构建三阴性乳腺癌4T1-BALB/c原位荷瘤小鼠,流式细胞术检测荷瘤小鼠血液、骨髓、肺组织内骨髓源性抑制细胞(MDSCs);通过苏木精-伊红(HE)染色确定小鼠肺转移微环境形成时间;利用蛋白质印迹(Western blotting)检测肺组织相关蛋白水平;通过对比各组小鼠肺转移微环境形成时间、肺组织骨髓及外周血中MDSCs数量、肺转移结节、肺转移组织相关蛋白探究西黄丸对乳腺癌肺转移的作用及机制。[结果]西黄丸及乳香、没药药对均在第14天对移植瘤有显著抑制作用;西黄丸能够延长乳腺癌肺转移出现时间(17 d vs. 14 d),且可以显著减少乳腺癌肺转移结节灶的数量;西黄丸能够抑制4T1-BALB/c荷瘤小鼠外周血及肺组织中MDSCs数量,且显著降低肺组织中基质金属蛋白酶9(MMP9)、S100A8/A9表达量。[结论]西黄丸可通过调控外周血及肺组织中MDSCs数量,抑制MMP9、S100A8/A9表达重塑乳腺癌肺转移微环境形成,达到抑制乳腺癌肺转移目的。研究为西黄丸临床抗肿瘤转移应用奠定基础。展开更多
文摘目的探讨膀胱癌MB49细胞来源的外泌体(exosomes)对MDSCs细胞扩增、活化的影响及机制。方法用超滤联合蔗糖重水密度梯度离心法分离纯化膀胱癌MB49细胞分泌的exosomes;电镜形态学分析及Western blotting鉴定;流式细胞仪检测MDSCs比例;ELISA检测VEGF和IL-6;RT-PCR和Western blotting检测cyclin D1、Arg-1 m RNA和蛋白的表达;Western blotting检测p-STAT3和p-NF-κB的变化。结果成功分离纯化得到膀胱癌MB49细胞分泌的exosomes。exosomes可促进MDSCs扩增及活化。实验组MDSCs比例明显升高;Cyclin D1及Arg-1 m RNA和蛋白的表达均上调;p-STAT3和p-NF-κB的表达也上调。结论膀胱癌MB49细胞来源的exosomes能促使MDSCs细胞扩增、活化。研究和分析MDSCs的免疫抑制机制,为疾病的治疗寻找行之有效的新靶点。
基金funded by the Medical University of Lublin,Poland,grant number DS 458.
文摘Objectives Chronic lymphocytic leukemia(CLL)is characterized by progressive immune dysregulation.Invariant natural killer T(iNKT)cells support immune surveillance,but the clinical relevance of their regulatory subsets remains unclear.FoxP3+regulatory iNKT cells(iNKTreg)and E4BP4+IL-10+(iNKT10)cells may reflect immunoregulatory changes associated with disease progression.The study aimed to quantify circulating iNKTreg and iNKT10 subsets and monocytic myeloid-derived suppressor cells(M-MDSCs)in treatment-naïve CLL patients and evaluate their associations with disease characteristics and time to first treatment(TTFT).Methods Peripheral blood samples from 60 untreated CLL patients and 20 healthy donors were analyzed by flow cytometry to determine iNKTreg and iNKT10 percentages,as well as indoleamine 2,3-dioxygenase(IDO)-expressing M-MDSCs.Receiver operating characteristic(ROC)curves and Cox proportional hazards models were used to assess prognostic significance.Results iNKTreg and iNKT10 percentages were significantly increased in CLL compared with healthy donors(p=0.002).Elevated iNKTreg frequencies were associated with zeta-chain-associated protein of 70 kD(ZAP-70)positivity(p=0.017),CD38 positivity(p=0.048),and treatment requirement during follow-up(p=0.016).Based on an ROC-derived cut-off of 9.6%(AUC=0.753),patients with iNKTreg≥9.6%had shorter TTFT(hazard ratio[HR]=2.71;95%confidence interval[CI],1.13–6.49;p=0.025),although the association was not retained in multivariate analysis(HR=1.27;95%CI,0.44–3.64;p=0.626).iNKTreg and iNKT10 percentages correlated positively with IDO+M-MDSCs(p=0.035 and p=0.044),but not with arginase-1(ARG1)or inducible nitric oxide synthase(NOS2).Conclusion Elevated iNKTreg levels reflect a more aggressive disease phenotype and associate with shorter TTFT in univariate analysis,supporting their exploration as complementary immunological biomarkers in CLL.Functional studies and validation in larger cohorts are needed to determine their prognostic and biological significance.
文摘[目的]探讨西黄丸对三阴性乳腺癌肺转移的机制。[方法]构建三阴性乳腺癌4T1-BALB/c原位荷瘤小鼠,流式细胞术检测荷瘤小鼠血液、骨髓、肺组织内骨髓源性抑制细胞(MDSCs);通过苏木精-伊红(HE)染色确定小鼠肺转移微环境形成时间;利用蛋白质印迹(Western blotting)检测肺组织相关蛋白水平;通过对比各组小鼠肺转移微环境形成时间、肺组织骨髓及外周血中MDSCs数量、肺转移结节、肺转移组织相关蛋白探究西黄丸对乳腺癌肺转移的作用及机制。[结果]西黄丸及乳香、没药药对均在第14天对移植瘤有显著抑制作用;西黄丸能够延长乳腺癌肺转移出现时间(17 d vs. 14 d),且可以显著减少乳腺癌肺转移结节灶的数量;西黄丸能够抑制4T1-BALB/c荷瘤小鼠外周血及肺组织中MDSCs数量,且显著降低肺组织中基质金属蛋白酶9(MMP9)、S100A8/A9表达量。[结论]西黄丸可通过调控外周血及肺组织中MDSCs数量,抑制MMP9、S100A8/A9表达重塑乳腺癌肺转移微环境形成,达到抑制乳腺癌肺转移目的。研究为西黄丸临床抗肿瘤转移应用奠定基础。
