Self-assembling carrier-free nanodrugs are attractive agents because they accumulate at tumor by an enhanced permeability and retention(EPR) effect without introduction of inactive substances,and some nanodrugs can al...Self-assembling carrier-free nanodrugs are attractive agents because they accumulate at tumor by an enhanced permeability and retention(EPR) effect without introduction of inactive substances,and some nanodrugs can alter the immune environment. We synthesized a peptidyl arginine deiminase 4(PAD4) molecular inhibitor, ZD-E-1 M. It could self-assembled into nanodrug ZD-E-1. Using confocal laser scanning microscopy, we observed its cellular colocalization, PAD4 activity and neutrophil extracellular traps(NETs) formation. The populations of immune cells and expression of immune-related proteins were determined by single-cell mass cytometry. ZD-E-1 formed nanoflowers in an acidic environment, whereas it formed nanospheres at pH 7.4. Accumulation of ZD-E-1 at tumor was pHresponsive because of its pH-dependent differences in the size and shape. It could enter the nucleus and bind to PAD4 to prolong the intracellular retention time. In mice, ZD-E-1 inhibited tumor growth and metastasis by inhibiting PAD4 activity and NETs formation. Besides, ZD-E-1 could regulate the ratio of immune cells in LLC tumor-bearing mice. Immunosuppressive proteins like LAG3 were suppressed,while IFN-γ and TNF-a as stimulators of tumor immune response were upregulated. Overall, ZD-E-1 is a self-assembling carrier-free nanodrug that responds to pH, inhibits PAD4 activity, blocks neutrophil extracellular traps formation, and improves the tumor immune microenvironment.展开更多
Objective:To study the correlation of serum sLAG-3, PARP-1 and CA50 levels with oncogene expression in surgically removed lesions in patients with gastric cancer.Methods: A total of 98 patients who were diagnosed with...Objective:To study the correlation of serum sLAG-3, PARP-1 and CA50 levels with oncogene expression in surgically removed lesions in patients with gastric cancer.Methods: A total of 98 patients who were diagnosed with gastric cancer in Zhouzhi County People's Hospital between June 2015 and March 2017 were selected as the gastric cancer group of the research, and 60 healthy volunteers who received physical examination during the same period were selected as control group of the research. The serum was collected from the two groups to determine sLAG-3, PARP-1 and CA50 levels;gastric cancer lesions and adjacent lesions were collected from gastric cancer group to determine the protein expression of PDCD4, RASSF1A, p16ink4a, Kiss-1, Eaf-2, CDC4, UHRF1, OCT4, Zeb-1 and c-jun.Results:Serum sLAG-3, PARP-1 and CA50 levels of gastric cancer group were significantly higher than those of control group, and the higher the TNM stage, the higher the serum sLAG-3, PARP-1 and CA50 levels;PDCD4, RASSF1A, p16ink4a, Kiss-1, Eaf-2 and CDC4 protein levels in gastric cancer lesions were significantly lower than those in adjacent lesions and negatively correlated with serum sLAG-3, PARP-1 and CA50 levels, while UHRF1, OCT4, Zeb-1 and c-jun protein levels in gastric cancer lesions were significantly higher than those in adjacent lesions and positively correlated with serum sLAG-3, PARP-1 and CA50 levels.Conclusions:The increase in serum sLAG-3, PARP-1 and CA50 levels in patients with gastric cancer is closely related to the pathological process of gastric cancer, deletion of tumor suppressor gene expression and increase of proto-oncogene expression.展开更多
目的:探讨三阴性乳腺癌(triple-negative breast cancer,TNBC)组织中淋巴细胞激活基因-3(lymphocyte-activation gene-3,LAG-3)、程序性死亡受体-1(programmed death-1,PD-1)、程序性死亡受体-1配体(programmed death ligand-1,PD-L1)...目的:探讨三阴性乳腺癌(triple-negative breast cancer,TNBC)组织中淋巴细胞激活基因-3(lymphocyte-activation gene-3,LAG-3)、程序性死亡受体-1(programmed death-1,PD-1)、程序性死亡受体-1配体(programmed death ligand-1,PD-L1)的表达和肿瘤浸润淋巴细胞(tumor infiltrating lymphocyte,TIL)计数的临床意义。方法:免疫组织化学法检测62例原发性TNBC组织和30例癌旁组织中LAG-3、PD-1、PD-L1的表达,苏木素-伊红法染色并计数TIL,分析四者与TNBC临床病理特征及预后的关系。结果:TNBC组织中LAG-3、PD-1和PD-L1表达显著高于癌旁组织(P<0.01);LAG-3表达与TNBC患者的淋巴结转移、Ki-67、PD-1、PD-L1表达和TIL计数有关(P<0.05);单因素分析显示,TNBC患者DFS与淋巴结转移、TNM分期、Ki-67、TIL、LAG-3^(+)PD-1^(+)、LAG-3^(+)PD-L1^(+)、LAG-3^(+)TIL^(low)有关(P<0.05);多因素分析显示,TNM分期、LAG-3^(+)PD-L1^(+)和TIL是TNBC患者预后的独立危险因素(P<0.05)。结论:TNM分期、LAG-3^(+)PD-L1^(+)和TIL与TNBC患者不良预后有关,特别是LAG-3和PD-L1结合共表达,可为免疫检查点双重阻滞在TNBC患者的临床应用中提供更多的理论依据。展开更多
Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell dea...Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell death protein-1(PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),can bind to their respective receptors and reduce tumor immunity in a variety of ways,including blocking immune cell activation signals.IC blockade(ICB)therapies targeting these checkpoint molecules have demonstrated significant clinical benefits.This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers.Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment.In this review,we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels,including epigenetic regulation,transcriptional regulation,and post-translational modifications.In addition,we provide a summary of the medications targeting various nodes in the regulatory pathway,and highlight the potential of newly identified IC molecules,focusing on their potential implications for cancer diagnostics and immunotherapy.展开更多
基金supported by the Beijing Municipal Colleges and Universities High Level Talents Introduction and Cultivate Project-Beijing Great Wall Scholar Program (CIT&TCD 20180332,China)。
文摘Self-assembling carrier-free nanodrugs are attractive agents because they accumulate at tumor by an enhanced permeability and retention(EPR) effect without introduction of inactive substances,and some nanodrugs can alter the immune environment. We synthesized a peptidyl arginine deiminase 4(PAD4) molecular inhibitor, ZD-E-1 M. It could self-assembled into nanodrug ZD-E-1. Using confocal laser scanning microscopy, we observed its cellular colocalization, PAD4 activity and neutrophil extracellular traps(NETs) formation. The populations of immune cells and expression of immune-related proteins were determined by single-cell mass cytometry. ZD-E-1 formed nanoflowers in an acidic environment, whereas it formed nanospheres at pH 7.4. Accumulation of ZD-E-1 at tumor was pHresponsive because of its pH-dependent differences in the size and shape. It could enter the nucleus and bind to PAD4 to prolong the intracellular retention time. In mice, ZD-E-1 inhibited tumor growth and metastasis by inhibiting PAD4 activity and NETs formation. Besides, ZD-E-1 could regulate the ratio of immune cells in LLC tumor-bearing mice. Immunosuppressive proteins like LAG3 were suppressed,while IFN-γ and TNF-a as stimulators of tumor immune response were upregulated. Overall, ZD-E-1 is a self-assembling carrier-free nanodrug that responds to pH, inhibits PAD4 activity, blocks neutrophil extracellular traps formation, and improves the tumor immune microenvironment.
文摘Objective:To study the correlation of serum sLAG-3, PARP-1 and CA50 levels with oncogene expression in surgically removed lesions in patients with gastric cancer.Methods: A total of 98 patients who were diagnosed with gastric cancer in Zhouzhi County People's Hospital between June 2015 and March 2017 were selected as the gastric cancer group of the research, and 60 healthy volunteers who received physical examination during the same period were selected as control group of the research. The serum was collected from the two groups to determine sLAG-3, PARP-1 and CA50 levels;gastric cancer lesions and adjacent lesions were collected from gastric cancer group to determine the protein expression of PDCD4, RASSF1A, p16ink4a, Kiss-1, Eaf-2, CDC4, UHRF1, OCT4, Zeb-1 and c-jun.Results:Serum sLAG-3, PARP-1 and CA50 levels of gastric cancer group were significantly higher than those of control group, and the higher the TNM stage, the higher the serum sLAG-3, PARP-1 and CA50 levels;PDCD4, RASSF1A, p16ink4a, Kiss-1, Eaf-2 and CDC4 protein levels in gastric cancer lesions were significantly lower than those in adjacent lesions and negatively correlated with serum sLAG-3, PARP-1 and CA50 levels, while UHRF1, OCT4, Zeb-1 and c-jun protein levels in gastric cancer lesions were significantly higher than those in adjacent lesions and positively correlated with serum sLAG-3, PARP-1 and CA50 levels.Conclusions:The increase in serum sLAG-3, PARP-1 and CA50 levels in patients with gastric cancer is closely related to the pathological process of gastric cancer, deletion of tumor suppressor gene expression and increase of proto-oncogene expression.
文摘目的:探讨三阴性乳腺癌(triple-negative breast cancer,TNBC)组织中淋巴细胞激活基因-3(lymphocyte-activation gene-3,LAG-3)、程序性死亡受体-1(programmed death-1,PD-1)、程序性死亡受体-1配体(programmed death ligand-1,PD-L1)的表达和肿瘤浸润淋巴细胞(tumor infiltrating lymphocyte,TIL)计数的临床意义。方法:免疫组织化学法检测62例原发性TNBC组织和30例癌旁组织中LAG-3、PD-1、PD-L1的表达,苏木素-伊红法染色并计数TIL,分析四者与TNBC临床病理特征及预后的关系。结果:TNBC组织中LAG-3、PD-1和PD-L1表达显著高于癌旁组织(P<0.01);LAG-3表达与TNBC患者的淋巴结转移、Ki-67、PD-1、PD-L1表达和TIL计数有关(P<0.05);单因素分析显示,TNBC患者DFS与淋巴结转移、TNM分期、Ki-67、TIL、LAG-3^(+)PD-1^(+)、LAG-3^(+)PD-L1^(+)、LAG-3^(+)TIL^(low)有关(P<0.05);多因素分析显示,TNM分期、LAG-3^(+)PD-L1^(+)和TIL是TNBC患者预后的独立危险因素(P<0.05)。结论:TNM分期、LAG-3^(+)PD-L1^(+)和TIL与TNBC患者不良预后有关,特别是LAG-3和PD-L1结合共表达,可为免疫检查点双重阻滞在TNBC患者的临床应用中提供更多的理论依据。
基金supported by the National Key Research and Development Program of China(No.2021YFC2700903)the National Natural Science Foundation of China(Nos.81672791 and 81872300)+2 种基金the Zhejiang Provincial Natural Science Fund for Distinguished Young Scholars of China(No.LR18C060002)the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(No.LHDMY22H160006)the ZJU-QILU Joint Research Institute and Qilu Group.
文摘Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell death protein-1(PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),can bind to their respective receptors and reduce tumor immunity in a variety of ways,including blocking immune cell activation signals.IC blockade(ICB)therapies targeting these checkpoint molecules have demonstrated significant clinical benefits.This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers.Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment.In this review,we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels,including epigenetic regulation,transcriptional regulation,and post-translational modifications.In addition,we provide a summary of the medications targeting various nodes in the regulatory pathway,and highlight the potential of newly identified IC molecules,focusing on their potential implications for cancer diagnostics and immunotherapy.
