The therapeutic efficacy of radioimmunotherapy against triple negative breast cancer(TNBC)is largely limited by the complicated tumor microenvironment(TME)and its immunosuppressive state.Thus developing a strategy to ...The therapeutic efficacy of radioimmunotherapy against triple negative breast cancer(TNBC)is largely limited by the complicated tumor microenvironment(TME)and its immunosuppressive state.Thus developing a strategy to reshape TME is expected to achieve highly efficient radioimmunotherapy.Therefore,we designed and synthesized a tellurium(Te)-driven maple leaf manganese carbonate nanotherapeutics(MnCO3@Te)by gas diffusion method,but also provided a chemical catalytic strategy in situ to augment ROS level and activate immune cells for improving cancer radioimmunotherapy.As expected,with the help of H2O2 in TEM,MnCO3@Te heterostructure with reversible Mn3+/Mn2+transition could catalyze the intracellular ROS overproduction to amplify radiotherapy.In addition,by virtue of the ability to scavenge H+in TME by carbonate group,MnCO3@Te directly promote the maturation of dendritic cells and macrophage M1 repolarization by stimulator of interferon genes(STING)pathway activation,resulting in remodeling immuno-microenvironment.As a result,MnCO3@Te synergized with radiotherapy and immune checkpoint blockade therapy effectively inhibited the breast cancer growth and lung metastasis in vivo.Collectively,these findings indicate that MnCO3@Te as an agonist,successfully overcome radioresistance and awaken immune systems,showing promising potential for solid tumor radioimmunotherapy.展开更多
Nucleic acid drugs are highly applicable for cancer immunotherapy with promising therapeutic effects, while targeting delivery of these drugs to disease lesions remains challenging. Cationic polymeric nanoparticles ha...Nucleic acid drugs are highly applicable for cancer immunotherapy with promising therapeutic effects, while targeting delivery of these drugs to disease lesions remains challenging. Cationic polymeric nanoparticles have paved the way for efficient delivery of nucleic acid drugs, and achieved stimuli-responsive disassembly in tumor microenvironment(TME). However, TME is highly heterogeneous between individuals, and most nanocarriers lack active-control over the release of loaded nucleic acid drugs, which will definitely reduce the therapeutic efficacy. Herein, we have developed a lightcontrollable charge-reversal nanoparticle(LCCN) with controlled release of polyinosinic-polycytidylic acid [Poly(I:C)] to treat triple negative breast cancer(TNBC) by enhanced photodynamic immunotherapy. The nanoparticles keep suitably positive charge for stable loading of Poly(I:C), while rapidly reverse to negative charge after near-infrared light irradiation to release Poly(I:C). LCCN-Poly(I:C) nanoparticles trigger effective phototoxicity and immunogenic cell death on 4 T1 tumor cells, elevate antitumor immune responses and inhibit the growth of primary and abscopal 4 T1 tumors in mice. The approach provides a promising strategy for controlled release of various nucleic acid-based immune modulators, which may enhance the efficacy of photodynamic immunotherapy against TNBC.展开更多
Triple-negative breast cancer(TNBC)is a pathological term used to identify invasive breast cancers that lack expression of estrogen and progesterone receptors and do not have pathologic overexpression of the HER2 rece...Triple-negative breast cancer(TNBC)is a pathological term used to identify invasive breast cancers that lack expression of estrogen and progesterone receptors and do not have pathologic overexpression of the HER2 receptor or harbor ERBB2 gene amplification.TNBC includes a collection of multiple distinct disease entities based upon genomic,transcriptomic and phenotypic characterization.Despite improved clinical outcomes with the development of novel therapeutics,TNBC still yields the worst prognosis among all clinical subtypes of breast cancer.We will systematically review evidence of the genomic evolution of TNBC,as well as potential mechanisms of disease progression and treatment resistance,defined in part by advances in next-generation DNA sequencing technology(including single cell sequencing),providing a new perspective on treatment strategies,and promise to reveal new potential therapeutic targets.Moreover,we review novel therapies aimed at homologous recombination deficiency,PI3 kinase/AKT/PTEN pathway activation,androgen receptor blockade,immune checkpoint inhibition,as well as antibody-drug conjugates engaging novel cell surface targets,including recent progress in pre-clinical and clinical studies which further validate the role of targeted therapies in TNBC.Despite major advances in treatment for TNBC,including FDA approval of 2 PARP inhibitors for metastatic TNBC,the crossing of the superiority boundary in a phase 3,placebo-controlled study of adjuvant olaparib in early-stage patients with germline BRCA-mutated high-risk HER2-negative early breast cancer,the FDA approval of 2 PD-(L)1 checkpoint antibodies for metastatic TNBC,and the FDA approval of the first antibody drug conjugate for TNBC,significant challenges remain.For example,despite the dawn of immunotherapy in metastatic TNBC,durable responses are limited to a small subset of patients,definitive biomarkers for patient selection are lacking,and the Oncology Drug Advisory Committee to the FDA has recently voted against approval of an anti-PD-1 checkpoint antibody high risk early-stage TNBC in the neoadjuvant setting.Also,despite early positive randomized phase 2 studies of AKT inhibition in metastatic TNBC,a recent phase 3 registration trial failed to validate earlier phase 2 data.Finally,we note that level one evidence for clinical efficacy of androgen receptor blockade in TNBC is still lacking.To meet these and other challenges,we will catalogue the ongoing exponential increase in interest in basic,translational,and clinical research to develop new treatment paradigms for TNBC.展开更多
Breast cancer is the most commonly diagnosed cancer type and the leading cause of cancer-related deaths among women worldwide.Previous studies have reported contradictory performance of chemokine CXC motif ligand 13(C...Breast cancer is the most commonly diagnosed cancer type and the leading cause of cancer-related deaths among women worldwide.Previous studies have reported contradictory performance of chemokine CXC motif ligand 13(CXCL13)in breast cancer.In this study,The Cancer Genome Atlas database analysis revealed that CXCL13 was overexpressed in various human cancers including breast carcinoma,and associated with good clinical prognosis in breast cancer.Flow cytometry detection also found upregulated intracellular CXCL13 expression in human breast cancer cell lines.To explore the possible role of CXCL13 in the breast cancer microenvironment,mouse triple negative breast cancer(TNBC)was lentivirally transfected to stably overexpress mouse CXCL13(4T1-CXCL13).Both parental 4T1 and 4T1-CXCL13 strains showed no in vitro or in vivo endogenous cell surface CXCR5 expression.In immune-competent BALB/c mice,the in vivo tumor growth of 4T1-CXCL13 was significantly inhibited and even completely eradicated,accompanied with increased infiltrations of CD4^(+),CD8^(+)T lymphocytes and CD11b^(+)CD11c^(+)DCs.Further investigations showed that CXCL13 expression in the 4T1 tumor microenvironment elicited long-term antitumor immune memory,and rejection of distal parental tumor.The antitumor activity of CXCL13 was remarkedly impaired in BALB/cA-nu nude mice,or in BALB/c mice with CD8^(+)T lymphocyte or NK cell depletion.Our investigation indicated that CXCL13 expression in TNBC triggered effective antitumor immunity by chemoattracting immune cell infiltrations and could be considered as a novel prognostic marker for TNBC.展开更多
目的分析最大径<2 cm三阴性乳腺癌(TNBC)与乳腺纤维腺瘤(FA)的超声图像特征和几何圆度,提高临床鉴别诊断TNBC的准确性。方法回顾性分析我院经手术病理证实的74例最大径<2 cm的TNBC(TNBC组)和125例FA(FA组)患者的超声图像,比较两...目的分析最大径<2 cm三阴性乳腺癌(TNBC)与乳腺纤维腺瘤(FA)的超声图像特征和几何圆度,提高临床鉴别诊断TNBC的准确性。方法回顾性分析我院经手术病理证实的74例最大径<2 cm的TNBC(TNBC组)和125例FA(FA组)患者的超声图像,比较两组年龄、病灶大小、形态、方位、边缘、回声模式、后方回声特征、钙化等特征,以及病灶几何圆度的差异。应用Logistic回归分析最大径<2 cm TNBC的独立影响因素,绘制受试者工作特征(ROC)曲线分析几何圆度对其的诊断效能。结果TNBC组平均年龄(47.3±10.7)岁,FA组(35.5±9.0)岁,差异有统计学意义(P<0.05)。与FA组比较,TNBC组病灶出现不规则形(49/74)、方位不平行(30/74)、边缘不光整(65/74)、后方回声增强(48/74)者更多,差异均有统计学意义(均P<0.05)。TNBC组BI-RADS 4类和5类病灶较FA组更多,差异均有统计学意义(均P<0.05)。TNBC组平均几何圆度81%±9%,大于FA组(66%±11%),差异有统计学意义(P<0.05)。Logistic回归分析显示,患者年龄>45岁(OR=7.81)、病灶形态不规则(OR=4.29)、方位不平行(OR=8.32)、后方回声增强(OR=7.54)、BI-RADS分类为4类(4A类:OR=1.06,4B类:OR=13.54,4C类:OR=31.92)和5类(OR=40.07),以及病灶几何圆度>80%(OR=71.62)是最大径<2 cm TNBC的独立影响因素。ROC曲线分析显示,诊断最大径<2 cm TNBC的几何圆度截断值为80%,曲线下面积为0.816,敏感性、特异性分别为77.2%、74.6%。结论与FA比较,最大径<2 cm的TNBC患者年纪多偏大,表现出更多可疑的超声特征和更大的几何圆度,有助于临床对二者进行鉴别诊断。展开更多
基金supported by National Science Fund for Distinguished Young Scholars(82225025)National Natural Science Foundation of China(21877049,32171296,32201166,82172088)+2 种基金Guangdong Natural Science Foundation(2020B1515120043)Guangdong Basic and Applied Basic Research Fund Project(No.2021A1515111027)K.C.Wong Education Foundation.
文摘The therapeutic efficacy of radioimmunotherapy against triple negative breast cancer(TNBC)is largely limited by the complicated tumor microenvironment(TME)and its immunosuppressive state.Thus developing a strategy to reshape TME is expected to achieve highly efficient radioimmunotherapy.Therefore,we designed and synthesized a tellurium(Te)-driven maple leaf manganese carbonate nanotherapeutics(MnCO3@Te)by gas diffusion method,but also provided a chemical catalytic strategy in situ to augment ROS level and activate immune cells for improving cancer radioimmunotherapy.As expected,with the help of H2O2 in TEM,MnCO3@Te heterostructure with reversible Mn3+/Mn2+transition could catalyze the intracellular ROS overproduction to amplify radiotherapy.In addition,by virtue of the ability to scavenge H+in TME by carbonate group,MnCO3@Te directly promote the maturation of dendritic cells and macrophage M1 repolarization by stimulator of interferon genes(STING)pathway activation,resulting in remodeling immuno-microenvironment.As a result,MnCO3@Te synergized with radiotherapy and immune checkpoint blockade therapy effectively inhibited the breast cancer growth and lung metastasis in vivo.Collectively,these findings indicate that MnCO3@Te as an agonist,successfully overcome radioresistance and awaken immune systems,showing promising potential for solid tumor radioimmunotherapy.
基金Financial supports from the National Natural Science Foundation of China(81903548,81690265,81803444,81521005 and 32070927)the Youth Innovation Promotion Association of CAS(2019283)+3 种基金the Strategic Priority Research Program of CAS(XDA12050307)Shandong Provincial Natural Science Foundation(ZR2019ZD25)the International Partnership Program of CAS(153631KYSB20190013)the Shanghai Sailing Program(19YF1457300)。
文摘Nucleic acid drugs are highly applicable for cancer immunotherapy with promising therapeutic effects, while targeting delivery of these drugs to disease lesions remains challenging. Cationic polymeric nanoparticles have paved the way for efficient delivery of nucleic acid drugs, and achieved stimuli-responsive disassembly in tumor microenvironment(TME). However, TME is highly heterogeneous between individuals, and most nanocarriers lack active-control over the release of loaded nucleic acid drugs, which will definitely reduce the therapeutic efficacy. Herein, we have developed a lightcontrollable charge-reversal nanoparticle(LCCN) with controlled release of polyinosinic-polycytidylic acid [Poly(I:C)] to treat triple negative breast cancer(TNBC) by enhanced photodynamic immunotherapy. The nanoparticles keep suitably positive charge for stable loading of Poly(I:C), while rapidly reverse to negative charge after near-infrared light irradiation to release Poly(I:C). LCCN-Poly(I:C) nanoparticles trigger effective phototoxicity and immunogenic cell death on 4 T1 tumor cells, elevate antitumor immune responses and inhibit the growth of primary and abscopal 4 T1 tumors in mice. The approach provides a promising strategy for controlled release of various nucleic acid-based immune modulators, which may enhance the efficacy of photodynamic immunotherapy against TNBC.
基金This work was supported by the Breast Cancer Research Foundation(116453).
文摘Triple-negative breast cancer(TNBC)is a pathological term used to identify invasive breast cancers that lack expression of estrogen and progesterone receptors and do not have pathologic overexpression of the HER2 receptor or harbor ERBB2 gene amplification.TNBC includes a collection of multiple distinct disease entities based upon genomic,transcriptomic and phenotypic characterization.Despite improved clinical outcomes with the development of novel therapeutics,TNBC still yields the worst prognosis among all clinical subtypes of breast cancer.We will systematically review evidence of the genomic evolution of TNBC,as well as potential mechanisms of disease progression and treatment resistance,defined in part by advances in next-generation DNA sequencing technology(including single cell sequencing),providing a new perspective on treatment strategies,and promise to reveal new potential therapeutic targets.Moreover,we review novel therapies aimed at homologous recombination deficiency,PI3 kinase/AKT/PTEN pathway activation,androgen receptor blockade,immune checkpoint inhibition,as well as antibody-drug conjugates engaging novel cell surface targets,including recent progress in pre-clinical and clinical studies which further validate the role of targeted therapies in TNBC.Despite major advances in treatment for TNBC,including FDA approval of 2 PARP inhibitors for metastatic TNBC,the crossing of the superiority boundary in a phase 3,placebo-controlled study of adjuvant olaparib in early-stage patients with germline BRCA-mutated high-risk HER2-negative early breast cancer,the FDA approval of 2 PD-(L)1 checkpoint antibodies for metastatic TNBC,and the FDA approval of the first antibody drug conjugate for TNBC,significant challenges remain.For example,despite the dawn of immunotherapy in metastatic TNBC,durable responses are limited to a small subset of patients,definitive biomarkers for patient selection are lacking,and the Oncology Drug Advisory Committee to the FDA has recently voted against approval of an anti-PD-1 checkpoint antibody high risk early-stage TNBC in the neoadjuvant setting.Also,despite early positive randomized phase 2 studies of AKT inhibition in metastatic TNBC,a recent phase 3 registration trial failed to validate earlier phase 2 data.Finally,we note that level one evidence for clinical efficacy of androgen receptor blockade in TNBC is still lacking.To meet these and other challenges,we will catalogue the ongoing exponential increase in interest in basic,translational,and clinical research to develop new treatment paradigms for TNBC.
基金Thisworkwas supported by theNationalNatural Science Foundation of China(grant No.81402354).
文摘Breast cancer is the most commonly diagnosed cancer type and the leading cause of cancer-related deaths among women worldwide.Previous studies have reported contradictory performance of chemokine CXC motif ligand 13(CXCL13)in breast cancer.In this study,The Cancer Genome Atlas database analysis revealed that CXCL13 was overexpressed in various human cancers including breast carcinoma,and associated with good clinical prognosis in breast cancer.Flow cytometry detection also found upregulated intracellular CXCL13 expression in human breast cancer cell lines.To explore the possible role of CXCL13 in the breast cancer microenvironment,mouse triple negative breast cancer(TNBC)was lentivirally transfected to stably overexpress mouse CXCL13(4T1-CXCL13).Both parental 4T1 and 4T1-CXCL13 strains showed no in vitro or in vivo endogenous cell surface CXCR5 expression.In immune-competent BALB/c mice,the in vivo tumor growth of 4T1-CXCL13 was significantly inhibited and even completely eradicated,accompanied with increased infiltrations of CD4^(+),CD8^(+)T lymphocytes and CD11b^(+)CD11c^(+)DCs.Further investigations showed that CXCL13 expression in the 4T1 tumor microenvironment elicited long-term antitumor immune memory,and rejection of distal parental tumor.The antitumor activity of CXCL13 was remarkedly impaired in BALB/cA-nu nude mice,or in BALB/c mice with CD8^(+)T lymphocyte or NK cell depletion.Our investigation indicated that CXCL13 expression in TNBC triggered effective antitumor immunity by chemoattracting immune cell infiltrations and could be considered as a novel prognostic marker for TNBC.
文摘目的分析最大径<2 cm三阴性乳腺癌(TNBC)与乳腺纤维腺瘤(FA)的超声图像特征和几何圆度,提高临床鉴别诊断TNBC的准确性。方法回顾性分析我院经手术病理证实的74例最大径<2 cm的TNBC(TNBC组)和125例FA(FA组)患者的超声图像,比较两组年龄、病灶大小、形态、方位、边缘、回声模式、后方回声特征、钙化等特征,以及病灶几何圆度的差异。应用Logistic回归分析最大径<2 cm TNBC的独立影响因素,绘制受试者工作特征(ROC)曲线分析几何圆度对其的诊断效能。结果TNBC组平均年龄(47.3±10.7)岁,FA组(35.5±9.0)岁,差异有统计学意义(P<0.05)。与FA组比较,TNBC组病灶出现不规则形(49/74)、方位不平行(30/74)、边缘不光整(65/74)、后方回声增强(48/74)者更多,差异均有统计学意义(均P<0.05)。TNBC组BI-RADS 4类和5类病灶较FA组更多,差异均有统计学意义(均P<0.05)。TNBC组平均几何圆度81%±9%,大于FA组(66%±11%),差异有统计学意义(P<0.05)。Logistic回归分析显示,患者年龄>45岁(OR=7.81)、病灶形态不规则(OR=4.29)、方位不平行(OR=8.32)、后方回声增强(OR=7.54)、BI-RADS分类为4类(4A类:OR=1.06,4B类:OR=13.54,4C类:OR=31.92)和5类(OR=40.07),以及病灶几何圆度>80%(OR=71.62)是最大径<2 cm TNBC的独立影响因素。ROC曲线分析显示,诊断最大径<2 cm TNBC的几何圆度截断值为80%,曲线下面积为0.816,敏感性、特异性分别为77.2%、74.6%。结论与FA比较,最大径<2 cm的TNBC患者年纪多偏大,表现出更多可疑的超声特征和更大的几何圆度,有助于临床对二者进行鉴别诊断。
