Background:Tumor-associated neutrophils(TANs)play a critical role in modulating immune responses and exhibit significant heterogeneity.Our previous study demonstrated that jagged canonical Notch ligand 2(JAG2)+TANs we...Background:Tumor-associated neutrophils(TANs)play a critical role in modulating immune responses and exhibit significant heterogeneity.Our previous study demonstrated that jagged canonical Notch ligand 2(JAG2)+TANs were associated with an immunosuppressive microenvironment in high-grade serous ovarian cancer(HGSOC),but the underlying mechanism remains unclear.This study aimed to elucidate the role of JAG2^(+)TANs in tumor immunosuppressive microenvironment in HGSOC.Methods:HGSOC samples were collected,with 274 samples constituting two independent cohorts(training and validation cohorts)and an additional 30 samples utilized to establish patient-derived tumor organoids(PDTOs).We characterized the number and phenotype of JAG2^(+)TANs by multiplex immunohistochemistry,flow cytometry,and single-cell RNA sequencing(scRNA-seq).We investigated the biological functions of JAG2 in immune evasion using in vitro co-culture systems,flow cytometry,tumor-bearing mouse models,and PDTOs.Results:JAG2^(+)TANs expressed elevated levels of immunosuppressive molecules,including programmed cell death ligand 1 and CD14,and had independent prognostic value for the overall survival of patients with HGSOC.scRNA-seq analysis revealed that JAG2^(+)TANs exhibited a terminally mature phenotype.The infiltration of JAG2^(+)TANs was positively correlated with the abundance of effector regulatory T cells(eTregs).Interaction with JAG2^(+)TANs skewed CD4+T cells towards an eTreg phenotype,a process that was suppressed by the Notch inhibitor LY3039478 and induced by recombinant Jagged2.Furthermore,we demonstrated that JAG2^(+)TANs enhanced Notch signaling activation,ultimately promoting recombination signal binding protein for immunoglobulin kappa J region(RBPJ)-induced differentiation of naïve CD4+T cells into eTregs.Clinically,JAG2^(+)TANs could serve as a biomarker for assessing immunotherapy resistance in various solid tumors.Pharmacological targeting of Notch signaling with LY3039478 or JAG2 neutralization antibodies enhanced the efficacy of programmed cell death protein 1(PD-1)monoclonal antibodies(mAbs)in both xenograft and PDTO models.Conclusions:The emergence of JAG2^(+)TANs is crucial for the differentiation of eTregs,which triggers immune evasion and resistance to anti-PD-1 therapy.Inhibiting Notch signaling with LY3039478 or JAG2 neutralization antibodies may overcome this anti-PD-1 resistance in HGSOC.展开更多
JAGS(Just Another Gibbs Sampler)是为弥补BUGS软件无法在Unix或Linux等非Windows系统上运行的缺陷而研发的编程软件,其自身独立拥有一套贝叶斯理论运算函数及公式,具有操作界面简单、与系统兼容好、运行流畅、且与其他编程软件具有良...JAGS(Just Another Gibbs Sampler)是为弥补BUGS软件无法在Unix或Linux等非Windows系统上运行的缺陷而研发的编程软件,其自身独立拥有一套贝叶斯理论运算函数及公式,具有操作界面简单、与系统兼容好、运行流畅、且与其他编程软件具有良好交互性等特点。然而,由于JAGS软件在结果数据读取、解读以及图形绘制方面存在功能性缺失,限制了其推广应用;通过R2jags、rjags及runjags程序包从R中调用JAGS软件则克服了这些缺陷。R2jags、rjags及runjags这3款程序包的工作原理均是在R语言的框架下通过调用JAGS软件来完成相关迭代运算,它们的功能结构基本相似,都具有操作简单、命令简洁、数据读取和结果汇总以及图形绘制功能较完善的特点,但在实践运用中仍存在差异。本文介绍了如何使用R软件通过R2jags、rjags及runjags程序包调用JAGS软件来实现网状Meta分析。展开更多
基金supported by the Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases,the Obstetrics and Gynecology Hospital,Fudan University,and Shanghai Cancer Center,Fudan Universityfunded by grants from the National Natural Science Foundation of China(82072881,82273205,82203665,82473274)+1 种基金Natural Science Foundation of Shanghai(23ZR1408300),Shanghai Science and Technology Innovation Action Plan(23Y11909500,23Y11901800)Shanghai Clinical Research Center for Gynecological Diseases(22MC1940200).
文摘Background:Tumor-associated neutrophils(TANs)play a critical role in modulating immune responses and exhibit significant heterogeneity.Our previous study demonstrated that jagged canonical Notch ligand 2(JAG2)+TANs were associated with an immunosuppressive microenvironment in high-grade serous ovarian cancer(HGSOC),but the underlying mechanism remains unclear.This study aimed to elucidate the role of JAG2^(+)TANs in tumor immunosuppressive microenvironment in HGSOC.Methods:HGSOC samples were collected,with 274 samples constituting two independent cohorts(training and validation cohorts)and an additional 30 samples utilized to establish patient-derived tumor organoids(PDTOs).We characterized the number and phenotype of JAG2^(+)TANs by multiplex immunohistochemistry,flow cytometry,and single-cell RNA sequencing(scRNA-seq).We investigated the biological functions of JAG2 in immune evasion using in vitro co-culture systems,flow cytometry,tumor-bearing mouse models,and PDTOs.Results:JAG2^(+)TANs expressed elevated levels of immunosuppressive molecules,including programmed cell death ligand 1 and CD14,and had independent prognostic value for the overall survival of patients with HGSOC.scRNA-seq analysis revealed that JAG2^(+)TANs exhibited a terminally mature phenotype.The infiltration of JAG2^(+)TANs was positively correlated with the abundance of effector regulatory T cells(eTregs).Interaction with JAG2^(+)TANs skewed CD4+T cells towards an eTreg phenotype,a process that was suppressed by the Notch inhibitor LY3039478 and induced by recombinant Jagged2.Furthermore,we demonstrated that JAG2^(+)TANs enhanced Notch signaling activation,ultimately promoting recombination signal binding protein for immunoglobulin kappa J region(RBPJ)-induced differentiation of naïve CD4+T cells into eTregs.Clinically,JAG2^(+)TANs could serve as a biomarker for assessing immunotherapy resistance in various solid tumors.Pharmacological targeting of Notch signaling with LY3039478 or JAG2 neutralization antibodies enhanced the efficacy of programmed cell death protein 1(PD-1)monoclonal antibodies(mAbs)in both xenograft and PDTO models.Conclusions:The emergence of JAG2^(+)TANs is crucial for the differentiation of eTregs,which triggers immune evasion and resistance to anti-PD-1 therapy.Inhibiting Notch signaling with LY3039478 or JAG2 neutralization antibodies may overcome this anti-PD-1 resistance in HGSOC.
文摘JAGS(Just Another Gibbs Sampler)是为弥补BUGS软件无法在Unix或Linux等非Windows系统上运行的缺陷而研发的编程软件,其自身独立拥有一套贝叶斯理论运算函数及公式,具有操作界面简单、与系统兼容好、运行流畅、且与其他编程软件具有良好交互性等特点。然而,由于JAGS软件在结果数据读取、解读以及图形绘制方面存在功能性缺失,限制了其推广应用;通过R2jags、rjags及runjags程序包从R中调用JAGS软件则克服了这些缺陷。R2jags、rjags及runjags这3款程序包的工作原理均是在R语言的框架下通过调用JAGS软件来完成相关迭代运算,它们的功能结构基本相似,都具有操作简单、命令简洁、数据读取和结果汇总以及图形绘制功能较完善的特点,但在实践运用中仍存在差异。本文介绍了如何使用R软件通过R2jags、rjags及runjags程序包调用JAGS软件来实现网状Meta分析。
