Sonodynamic therapy(SDT)can potentially induce immunogenic cell death in tumor cells,leading to the release of ATP,and facilitating the initiation of an immune response.Nevertheless,the enzymes CD39 and CD73 can swift...Sonodynamic therapy(SDT)can potentially induce immunogenic cell death in tumor cells,leading to the release of ATP,and facilitating the initiation of an immune response.Nevertheless,the enzymes CD39 and CD73 can swiftly convert ATP into immunosuppressive adenosine(ADO),resulting in an immunosuppressive tumor microenvironment(TME).This study introduced a nanomedicine(QD/POM1@NP@M)engineered to reprogram TME by modulating the CD39/CD73/ADO pathway.The nanomedicine encapsulated sonosensitizers silver sulfide quantum dots,and the CD39 inhibitor POM1,while also incorporating homologous tumor cell membranes to enhance targeting capabilities.This integrated approach,on the one hand,stimulates the release of ATP via SDT,thereby initiating the immune response.In addition,it reduced the accumulation of ADO by inhibiting CD39 activity,which ameliorated the immunosuppressive TME.Upon administration,the nanomedicine demonstrated substantial anti-tumor efficacy by facilitating the infiltration of anti-tumor immune cells,while reducing the immunosuppressive cells.This modulation effectively transformed the TME from an immunologically“cold”state to a“hot”state.Furthermore,combined with the checkpoint inhibitorα-PDL1,the nanomedicine augmented systemic anti-tumor immunity and promoted the establishment of long-term immune memory.This study provides an innovative strategy for combining non-invasive SDT and ATP-driven immunotherapy,offering new ideas for future cancer treatment.展开更多
调节性T细胞(regulatory T cell, Treg)是一类具有免疫抑制功能的T细胞亚群。表达于Treg细胞表面的CD39和CD73可将细胞外的三磷酸腺苷(ATP)依次分解为腺苷,进而调节靶细胞的功能,发挥免疫抑制功能。大量研究显示Treg细胞在过敏性疾病中...调节性T细胞(regulatory T cell, Treg)是一类具有免疫抑制功能的T细胞亚群。表达于Treg细胞表面的CD39和CD73可将细胞外的三磷酸腺苷(ATP)依次分解为腺苷,进而调节靶细胞的功能,发挥免疫抑制功能。大量研究显示Treg细胞在过敏性疾病中发挥重要作用,本文对Treg 细胞CD39-CD73-腺苷通路在过敏性疾病中的作用机制进行综述,为疾病治疗探究潜在的靶点。展开更多
目的:探讨CD39和CD73阳性的CD4+CD25+Foxp3+T淋巴细胞(Treg细胞)对支气管哮喘(简称哮喘)小鼠气道炎症的影响。方法:将16只BALB/c成年雌性小鼠随机分为哮喘组(n=8)和对照组(n=8)。用卵清蛋白进行哮喘造模后,取小鼠血清检测总Ig E,采用高...目的:探讨CD39和CD73阳性的CD4+CD25+Foxp3+T淋巴细胞(Treg细胞)对支气管哮喘(简称哮喘)小鼠气道炎症的影响。方法:将16只BALB/c成年雌性小鼠随机分为哮喘组(n=8)和对照组(n=8)。用卵清蛋白进行哮喘造模后,取小鼠血清检测总Ig E,采用高效液相色谱法行支气管肺泡灌洗液上清液三磷酸腺苷(adenosine-triphosphate,ATP)检测,取左肺组织行苏木精-伊红(hematoxylin eosin,HE)染色,观察小鼠肺组织的炎症改变;右肺上叶行CD39 m RNA、CD73 m RNA、Foxp3 m RNA检测;余右肺制成单细胞悬液,采用流式细胞术检测CD39+Treg和CD73+Treg细胞数量,计算其占Treg细胞百分比。结果 :哮喘组小鼠的血清总Ig E较对照组显著上升(P<0.01),支气管肺泡灌洗液中ATP较对照组升高(P<0.05),病理组织切片检查发现肺部炎症改变明显。哮喘组小鼠肺组织中CD39m RNA、CD73 m RNA、Foxp3 m RNA表达量分别为(0.54±0.11)×10-3、(1.11±0.36)×10-3、(0.08±0.03)×10-3,对照组则分别为(0.88±0.25)×10-3、(1.88±0.37)×10-3、(0.11±0.02)×10-3,2组间差异有统计学意义(P均<0.05)。流式细胞术检测发现,哮喘组小鼠肺组织的CD39+Treg、CD73+Treg细胞百分比较对照组略有下降趋势,但差异尚无统计学意义。结论:肺局部CD39+Treg和CD73+Treg细胞数量减少和(或)功能障碍导致的细胞外ATP清除率降低,可能是哮喘气道炎症发生的重要机制之一。展开更多
Tolerogenic dendritic cells(tol DCs)facilitate the suppression of autoimmune responses by differentiating regulatory T cells(Treg).The dysfunction of immunotolerance results in the development of autoimmune diseases,s...Tolerogenic dendritic cells(tol DCs)facilitate the suppression of autoimmune responses by differentiating regulatory T cells(Treg).The dysfunction of immunotolerance results in the development of autoimmune diseases,such as rheumatoid arthritis(RA).As multipotent progenitor cells,mesenchymal stem cells(MSCs),can regulate dendritic cells(DCs)to restore their immunosuppressive function and prevent disease development.However,the underlying mechanisms of MSCs in regulating DCs still need to be better defined.Simultaneously,the delivery system for MSCs also influences their function.Herein,MSCs are encapsulated in alginate hydrogel to improve cell survival and retention in situ,maximizing efficacy in vivo.The three-dimensional co-culture of encapsulated MSCs with DCs demonstrates that MSCs can inhibit the maturation of DCs and the secretion of pro-inflammatory cytokines.In the collagen-induced arthritis(CIA)mice model,alginate hydrogel encapsulated MSCs induce a significantly higher expression of CD39^(+)CD73^(+)on MSCs.These enzymes hydrolyze ATP to adenosine and activate A_(2A/2B)receptors on immature DCs,further promoting the phenotypic transformation of DCs to tol DCs and regulating naive T cells to Tregs.Therefore,encapsulated MSCs obviously alleviate the inflammatory response and prevent CIA progression.This finding clarifies the mechanism of MSCs-DCs crosstalk in eliciting the immunosuppression effect and provides insights into hydrogel-promoted stem cell therapy for autoimmune diseases.展开更多
基金supported by the National Natural Science Foundation of China(No.82472127 and No.82300598).The Fundamental Research Funds for the Central Universities,China(No.xtr052023008)Shaanxi Province Key Research and Development Program(2023-YBSF-072,2024JC-YBMS-664,China)+1 种基金Xi'an Science and Technology Plan Project(24YXYJ0143,China)the Young Talent Support Plan of Xi'an Jiaotong University,China(No.YX6J001).
文摘Sonodynamic therapy(SDT)can potentially induce immunogenic cell death in tumor cells,leading to the release of ATP,and facilitating the initiation of an immune response.Nevertheless,the enzymes CD39 and CD73 can swiftly convert ATP into immunosuppressive adenosine(ADO),resulting in an immunosuppressive tumor microenvironment(TME).This study introduced a nanomedicine(QD/POM1@NP@M)engineered to reprogram TME by modulating the CD39/CD73/ADO pathway.The nanomedicine encapsulated sonosensitizers silver sulfide quantum dots,and the CD39 inhibitor POM1,while also incorporating homologous tumor cell membranes to enhance targeting capabilities.This integrated approach,on the one hand,stimulates the release of ATP via SDT,thereby initiating the immune response.In addition,it reduced the accumulation of ADO by inhibiting CD39 activity,which ameliorated the immunosuppressive TME.Upon administration,the nanomedicine demonstrated substantial anti-tumor efficacy by facilitating the infiltration of anti-tumor immune cells,while reducing the immunosuppressive cells.This modulation effectively transformed the TME from an immunologically“cold”state to a“hot”state.Furthermore,combined with the checkpoint inhibitorα-PDL1,the nanomedicine augmented systemic anti-tumor immunity and promoted the establishment of long-term immune memory.This study provides an innovative strategy for combining non-invasive SDT and ATP-driven immunotherapy,offering new ideas for future cancer treatment.
文摘调节性T细胞(regulatory T cell, Treg)是一类具有免疫抑制功能的T细胞亚群。表达于Treg细胞表面的CD39和CD73可将细胞外的三磷酸腺苷(ATP)依次分解为腺苷,进而调节靶细胞的功能,发挥免疫抑制功能。大量研究显示Treg细胞在过敏性疾病中发挥重要作用,本文对Treg 细胞CD39-CD73-腺苷通路在过敏性疾病中的作用机制进行综述,为疾病治疗探究潜在的靶点。
文摘目的:探讨CD39和CD73阳性的CD4+CD25+Foxp3+T淋巴细胞(Treg细胞)对支气管哮喘(简称哮喘)小鼠气道炎症的影响。方法:将16只BALB/c成年雌性小鼠随机分为哮喘组(n=8)和对照组(n=8)。用卵清蛋白进行哮喘造模后,取小鼠血清检测总Ig E,采用高效液相色谱法行支气管肺泡灌洗液上清液三磷酸腺苷(adenosine-triphosphate,ATP)检测,取左肺组织行苏木精-伊红(hematoxylin eosin,HE)染色,观察小鼠肺组织的炎症改变;右肺上叶行CD39 m RNA、CD73 m RNA、Foxp3 m RNA检测;余右肺制成单细胞悬液,采用流式细胞术检测CD39+Treg和CD73+Treg细胞数量,计算其占Treg细胞百分比。结果 :哮喘组小鼠的血清总Ig E较对照组显著上升(P<0.01),支气管肺泡灌洗液中ATP较对照组升高(P<0.05),病理组织切片检查发现肺部炎症改变明显。哮喘组小鼠肺组织中CD39m RNA、CD73 m RNA、Foxp3 m RNA表达量分别为(0.54±0.11)×10-3、(1.11±0.36)×10-3、(0.08±0.03)×10-3,对照组则分别为(0.88±0.25)×10-3、(1.88±0.37)×10-3、(0.11±0.02)×10-3,2组间差异有统计学意义(P均<0.05)。流式细胞术检测发现,哮喘组小鼠肺组织的CD39+Treg、CD73+Treg细胞百分比较对照组略有下降趋势,但差异尚无统计学意义。结论:肺局部CD39+Treg和CD73+Treg细胞数量减少和(或)功能障碍导致的细胞外ATP清除率降低,可能是哮喘气道炎症发生的重要机制之一。
基金supported by the National Key R&D Program of China(No.2020YFA0908004)the National Natural Science Foundation of China(Nos.82293684,82293680,82273936,82273929)+1 种基金CAMS Innovation Fund for Medical Science(No.2021-I2M-1-028,2022-I2M-2-002,2022-I2M-1-014,China)Natural Science Fund for Distinguished Young Scholars of Tianjin(No.21JCJQJC00020,China)。
文摘Tolerogenic dendritic cells(tol DCs)facilitate the suppression of autoimmune responses by differentiating regulatory T cells(Treg).The dysfunction of immunotolerance results in the development of autoimmune diseases,such as rheumatoid arthritis(RA).As multipotent progenitor cells,mesenchymal stem cells(MSCs),can regulate dendritic cells(DCs)to restore their immunosuppressive function and prevent disease development.However,the underlying mechanisms of MSCs in regulating DCs still need to be better defined.Simultaneously,the delivery system for MSCs also influences their function.Herein,MSCs are encapsulated in alginate hydrogel to improve cell survival and retention in situ,maximizing efficacy in vivo.The three-dimensional co-culture of encapsulated MSCs with DCs demonstrates that MSCs can inhibit the maturation of DCs and the secretion of pro-inflammatory cytokines.In the collagen-induced arthritis(CIA)mice model,alginate hydrogel encapsulated MSCs induce a significantly higher expression of CD39^(+)CD73^(+)on MSCs.These enzymes hydrolyze ATP to adenosine and activate A_(2A/2B)receptors on immature DCs,further promoting the phenotypic transformation of DCs to tol DCs and regulating naive T cells to Tregs.Therefore,encapsulated MSCs obviously alleviate the inflammatory response and prevent CIA progression.This finding clarifies the mechanism of MSCs-DCs crosstalk in eliciting the immunosuppression effect and provides insights into hydrogel-promoted stem cell therapy for autoimmune diseases.
