Photodynamic therapy(PDT)has limited effects in treating metastatic breast cancer.Immune checkpoints can deplete the function of immune cells;however,the expression of immune checkpoints after PDT is unclear.This stud...Photodynamic therapy(PDT)has limited effects in treating metastatic breast cancer.Immune checkpoints can deplete the function of immune cells;however,the expression of immune checkpoints after PDT is unclear.This study investigates whether the limited e±cacy of PDT is due to upregulated immune checkpoints and tries to combine the PDT and immune checkpoint inhibitor to observe the e±cacy.A metastatic breast cancer model was treated by PDT mediated by hematoporphyrin derivatives(HpD-PDT).The anti-tumor effect of HpD-PDT was observed,as well as CD4þT,CD8þT and calreticulin(CRT)by immunohistochemistry and immunofluorescence.Immune checkpoints on T cells were analyzed byflow cytometry after HpD-PDT.When combining PDT with immune checkpoint inhibitors,the antitumor effect and immune effect were assessed.For HpD-PDT at 100 mW/cm2 and 40,60 and 80 J/cm2,primary tumors were suppressed and CD4þT,CD8þT and CRT were elevated;however,distant tumors couldn't be inhibited and survival could not be prolonged.Immune checkpoints on T cells,especially PD1 and LAG-3 after HpD-PDT,were upregulated,which may explain the reason for the limited HpD-PDT effect.After PDT combined with anti-PD1 antibody,but not with anti-LAG-3 antibody,both the primary and distant tumors were signi-cantly inhibited and the survival time was prolonged,additionally,CD4þT,CD8þT,IFN-þCD4þT and TNF-þCD4þT cells were signi-cantly increased compared with HpD-PDT.HpD-PDT could not combat metastatic breast cancer.PD1 and LAG-3 were upregulated after HpD-PDT.Anti-PD1 antibody,but not anti-LAG-3 antibody,could augment the antitumor effect of HpD-PDT for treating metastatic breast cancer.展开更多
Bacterial antitumor therapy has great application potential given its unique characteristics,including genetic manipulation, tumor targeting specificity and immune system modulation. However,the nonnegligible side eff...Bacterial antitumor therapy has great application potential given its unique characteristics,including genetic manipulation, tumor targeting specificity and immune system modulation. However,the nonnegligible side effects and limited efficacy of clinical treatment limit their biomedical applications. Engineered bacteria for therapeutic applications ideally need to avoid their accumulation in normal organs and possess potent antitumor activity. Here, we show that macrophage-mediated tumor-targeted delivery of Salmonella typhimurium VNP20009 can effectively reduce the toxicity caused by administrating VNP20009 alone in a melanoma mouse model. This benefits from tumor-induced chemotaxis for macrophages combined with their slow release of loaded strains. Inspired by changes in the tumor microenvironment, including a decrease in intratumoral dysfunctional CD8+T cells and an increase in PDL1 on the tumor cell surface, macrophages were loaded with the engineered strain VNP-PD1nb, which can express and secrete anti-PD1 nanoantibodies after they are released from macrophages. This novel triple-combined immunotherapy significantly inhibited melanoma tumors by reactivating the tumor microenvironment by increasing immune cell infiltration, inhibiting tumor cell proliferation, remodeling TAMs to an M1-like phenotype and prominently activating CD8+T cells. These data suggest that novel combination immunotherapy is expected to be a breakthrough relative to single immunotherapy.展开更多
本文通过建立肿瘤免疫微环境多尺度数学模型,结合小鼠实验数据,探讨了前列腺素E2受体4亚型(Prostaglandin E2 Receptor 4,EP4)拮抗剂MF-766和抗程序性细胞死亡蛋白1(Anti-programmed Cell Death Protein 1,Anti-PD-1)联合治疗对肿瘤免...本文通过建立肿瘤免疫微环境多尺度数学模型,结合小鼠实验数据,探讨了前列腺素E2受体4亚型(Prostaglandin E2 Receptor 4,EP4)拮抗剂MF-766和抗程序性细胞死亡蛋白1(Anti-programmed Cell Death Protein 1,Anti-PD-1)联合治疗对肿瘤免疫微环境及肿瘤生长的调控机制。模型定量分析了免疫抑制细胞、效应性免疫细胞以及细胞因子的动态变化,揭示了联合治疗在降低髓源性抑制细胞(Myeloid-derived Suppressor Cells,MDSCs)浓度和增强效应性免疫细胞功能中的协同作用。实验验证表明,模型能够准确描述肿瘤体积的动态变化及药物的免疫调节效应,并揭示了药物剂量与用药间隔对治疗效果的非线性影响。基于此模型的模拟结果,本文不仅加深了对肿瘤转移机制的理解,还为优化免疫治疗的剂量和用药策略提供了理论依据,为精准治疗的设计与推进奠定了坚实基础。展开更多
After that the era of chemotherapy in the treatment of solid tumors have been overcome by the "translational era", with the innovation introduced by targeted therapies, medical oncology is currently looking ...After that the era of chemotherapy in the treatment of solid tumors have been overcome by the "translational era", with the innovation introduced by targeted therapies, medical oncology is currently looking at the dawn of a new "immunotherapy era" with the advent of immune checkpoint inhibitors(CKI) antibodies.The onset of PD-1/PD-L1 targeted therapy has demonstrated the importance of this axis in the immune escape across almost all human cancers.The new CKI allowed to significantly prolong survival and to generate durable response, demonstrating remarkable efficacy in a wide range of cancer types.The aim of this article is to review the most up to date literature about the clinical effectiveness of CKI antibodies targeting PD-1/PD-L1 axis for the treatment of advanced solid tumors and to explore transversal challenges in the immune checkpoint blockade.展开更多
基金supported by the National Key Research and Development Program of China[2018YFB0407200]National Natural Science Foundation of China[61975239]Medical and Health Technology Innovation Project of the Chinese Academy of Medical Sciences[2019-I2M-5061].
文摘Photodynamic therapy(PDT)has limited effects in treating metastatic breast cancer.Immune checkpoints can deplete the function of immune cells;however,the expression of immune checkpoints after PDT is unclear.This study investigates whether the limited e±cacy of PDT is due to upregulated immune checkpoints and tries to combine the PDT and immune checkpoint inhibitor to observe the e±cacy.A metastatic breast cancer model was treated by PDT mediated by hematoporphyrin derivatives(HpD-PDT).The anti-tumor effect of HpD-PDT was observed,as well as CD4þT,CD8þT and calreticulin(CRT)by immunohistochemistry and immunofluorescence.Immune checkpoints on T cells were analyzed byflow cytometry after HpD-PDT.When combining PDT with immune checkpoint inhibitors,the antitumor effect and immune effect were assessed.For HpD-PDT at 100 mW/cm2 and 40,60 and 80 J/cm2,primary tumors were suppressed and CD4þT,CD8þT and CRT were elevated;however,distant tumors couldn't be inhibited and survival could not be prolonged.Immune checkpoints on T cells,especially PD1 and LAG-3 after HpD-PDT,were upregulated,which may explain the reason for the limited HpD-PDT effect.After PDT combined with anti-PD1 antibody,but not with anti-LAG-3 antibody,both the primary and distant tumors were signi-cantly inhibited and the survival time was prolonged,additionally,CD4þT,CD8þT,IFN-þCD4þT and TNF-þCD4þT cells were signi-cantly increased compared with HpD-PDT.HpD-PDT could not combat metastatic breast cancer.PD1 and LAG-3 were upregulated after HpD-PDT.Anti-PD1 antibody,but not anti-LAG-3 antibody,could augment the antitumor effect of HpD-PDT for treating metastatic breast cancer.
基金supported in part by grants from the National Natural Sciences Foundation of China (82130106)Jiangsu Provincial Department of Science and Technology (BK20192005, China)+1 种基金Changzhou Bureau of Science and Technology (CJ20210024, CZ20210010, China)Jiangsu TargetPharma Laboratories Inc., China
文摘Bacterial antitumor therapy has great application potential given its unique characteristics,including genetic manipulation, tumor targeting specificity and immune system modulation. However,the nonnegligible side effects and limited efficacy of clinical treatment limit their biomedical applications. Engineered bacteria for therapeutic applications ideally need to avoid their accumulation in normal organs and possess potent antitumor activity. Here, we show that macrophage-mediated tumor-targeted delivery of Salmonella typhimurium VNP20009 can effectively reduce the toxicity caused by administrating VNP20009 alone in a melanoma mouse model. This benefits from tumor-induced chemotaxis for macrophages combined with their slow release of loaded strains. Inspired by changes in the tumor microenvironment, including a decrease in intratumoral dysfunctional CD8+T cells and an increase in PDL1 on the tumor cell surface, macrophages were loaded with the engineered strain VNP-PD1nb, which can express and secrete anti-PD1 nanoantibodies after they are released from macrophages. This novel triple-combined immunotherapy significantly inhibited melanoma tumors by reactivating the tumor microenvironment by increasing immune cell infiltration, inhibiting tumor cell proliferation, remodeling TAMs to an M1-like phenotype and prominently activating CD8+T cells. These data suggest that novel combination immunotherapy is expected to be a breakthrough relative to single immunotherapy.
文摘本文通过建立肿瘤免疫微环境多尺度数学模型,结合小鼠实验数据,探讨了前列腺素E2受体4亚型(Prostaglandin E2 Receptor 4,EP4)拮抗剂MF-766和抗程序性细胞死亡蛋白1(Anti-programmed Cell Death Protein 1,Anti-PD-1)联合治疗对肿瘤免疫微环境及肿瘤生长的调控机制。模型定量分析了免疫抑制细胞、效应性免疫细胞以及细胞因子的动态变化,揭示了联合治疗在降低髓源性抑制细胞(Myeloid-derived Suppressor Cells,MDSCs)浓度和增强效应性免疫细胞功能中的协同作用。实验验证表明,模型能够准确描述肿瘤体积的动态变化及药物的免疫调节效应,并揭示了药物剂量与用药间隔对治疗效果的非线性影响。基于此模型的模拟结果,本文不仅加深了对肿瘤转移机制的理解,还为优化免疫治疗的剂量和用药策略提供了理论依据,为精准治疗的设计与推进奠定了坚实基础。
文摘After that the era of chemotherapy in the treatment of solid tumors have been overcome by the "translational era", with the innovation introduced by targeted therapies, medical oncology is currently looking at the dawn of a new "immunotherapy era" with the advent of immune checkpoint inhibitors(CKI) antibodies.The onset of PD-1/PD-L1 targeted therapy has demonstrated the importance of this axis in the immune escape across almost all human cancers.The new CKI allowed to significantly prolong survival and to generate durable response, demonstrating remarkable efficacy in a wide range of cancer types.The aim of this article is to review the most up to date literature about the clinical effectiveness of CKI antibodies targeting PD-1/PD-L1 axis for the treatment of advanced solid tumors and to explore transversal challenges in the immune checkpoint blockade.
