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
Gamma delta(γδ)T cells and invariant natural killer T(iNKT)cells are unconventional T cells with limited T cell receptor(TCR)diversity.Both can recognize lipid or non-peptide antigens,often through cluster of differ...Gamma delta(γδ)T cells and invariant natural killer T(iNKT)cells are unconventional T cells with limited T cell receptor(TCR)diversity.Both can recognize lipid or non-peptide antigens,often through cluster of differentiation 1d(CD1d),rapidly produce cytokines,express natural killer(NK)cell markers,and are mainly found in mucosal and barrier tissues.Acting as a bridge between innate and adaptive immunity,they show great promise for cancer immunotherapy.DevelopingγδT and iNKT cells for treatment involves shared features like thymic origin,MHC-independent recognition,rapid cytotoxicity,low graft-vs.-host disease(GvHD)risk,ex vivo expansion,and genetic modification,making them suitable for adoptive cell therapies.While their mechanisms are similar,iNKT cells rely on CD1d-mediated antigen presentation,provided by CD1d-expressing antigen-presenting cells(APCs)or engineered cell lines,to activate their invariant TCR and expand effectively.Chimeric antigen receptors(CAR)-induced functional activations make these cell types viable alternatives to conventional cell-based or CAR-T therapies with additional safety benefits.Early clinical trials have shown encouraging results,and their completion will confirm their potential for future treatments.This review explores the biology and mechanisms ofγδT and iNKT cells,focusing on how APCs,cytokines,feeder cells,and CARs contribute to boosting their cytotoxic function,cytokine production,and expansion,enhancing their promise as cancer immunotherapies.It also explores the advancements and challenges in developingγδT and iNKT cell-based immunotherapies,with preclinical and early clinical outcomes offering promising insights.展开更多
目的检测慢性乙型病毒性肝炎患者外周血中iNKT细胞比例、细胞因子分泌能力以及其表面程序性死亡因子1(programmed death 1,PD-1)的表达情况。方法采集慢性乙型肝炎患者外周血,利用CD3、TCR Vα24、TCR Vβ11、CD279单克隆抗体标记后经...目的检测慢性乙型病毒性肝炎患者外周血中iNKT细胞比例、细胞因子分泌能力以及其表面程序性死亡因子1(programmed death 1,PD-1)的表达情况。方法采集慢性乙型肝炎患者外周血,利用CD3、TCR Vα24、TCR Vβ11、CD279单克隆抗体标记后经流式细胞术直接检测iNKT细胞比例及其PD-1表达比例;采用PMA+Ionomycin体外活化iNKT细胞后流式细胞术检测其胞内IFN-γ分泌情况。结果慢性乙型肝炎患者外周血iNKT细胞比例[(0.09±0.04)%]与健康对照者[(0.11±0.07)%]相比无明显差异,但体外活化后胞内IFN-γ分泌量减少[(24.64±7.71)%vs(42.35±11.60)%],且iNKT细胞PD-1表达升高[(36.7±9.7)%vs(16.2±5.4)%]。结论慢性乙型肝炎患者外周血iNKT细胞功能的下降可能与其表面负性刺激分子PD-1表达上调密切相关。展开更多
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Gamma delta(γδ)T cells and invariant natural killer T(iNKT)cells are unconventional T cells with limited T cell receptor(TCR)diversity.Both can recognize lipid or non-peptide antigens,often through cluster of differentiation 1d(CD1d),rapidly produce cytokines,express natural killer(NK)cell markers,and are mainly found in mucosal and barrier tissues.Acting as a bridge between innate and adaptive immunity,they show great promise for cancer immunotherapy.DevelopingγδT and iNKT cells for treatment involves shared features like thymic origin,MHC-independent recognition,rapid cytotoxicity,low graft-vs.-host disease(GvHD)risk,ex vivo expansion,and genetic modification,making them suitable for adoptive cell therapies.While their mechanisms are similar,iNKT cells rely on CD1d-mediated antigen presentation,provided by CD1d-expressing antigen-presenting cells(APCs)or engineered cell lines,to activate their invariant TCR and expand effectively.Chimeric antigen receptors(CAR)-induced functional activations make these cell types viable alternatives to conventional cell-based or CAR-T therapies with additional safety benefits.Early clinical trials have shown encouraging results,and their completion will confirm their potential for future treatments.This review explores the biology and mechanisms ofγδT and iNKT cells,focusing on how APCs,cytokines,feeder cells,and CARs contribute to boosting their cytotoxic function,cytokine production,and expansion,enhancing their promise as cancer immunotherapies.It also explores the advancements and challenges in developingγδT and iNKT cell-based immunotherapies,with preclinical and early clinical outcomes offering promising insights.
文摘目的检测慢性乙型病毒性肝炎患者外周血中iNKT细胞比例、细胞因子分泌能力以及其表面程序性死亡因子1(programmed death 1,PD-1)的表达情况。方法采集慢性乙型肝炎患者外周血,利用CD3、TCR Vα24、TCR Vβ11、CD279单克隆抗体标记后经流式细胞术直接检测iNKT细胞比例及其PD-1表达比例;采用PMA+Ionomycin体外活化iNKT细胞后流式细胞术检测其胞内IFN-γ分泌情况。结果慢性乙型肝炎患者外周血iNKT细胞比例[(0.09±0.04)%]与健康对照者[(0.11±0.07)%]相比无明显差异,但体外活化后胞内IFN-γ分泌量减少[(24.64±7.71)%vs(42.35±11.60)%],且iNKT细胞PD-1表达升高[(36.7±9.7)%vs(16.2±5.4)%]。结论慢性乙型肝炎患者外周血iNKT细胞功能的下降可能与其表面负性刺激分子PD-1表达上调密切相关。
