The immunosuppressive tumor microenvironment(TME)of cancer strongly hinders the anti-tumor immune responses,thereby resulting in disappointing responses to immunotherapy.Chemoattractive and promotive traits of chemoki...The immunosuppressive tumor microenvironment(TME)of cancer strongly hinders the anti-tumor immune responses,thereby resulting in disappointing responses to immunotherapy.Chemoattractive and promotive traits of chemokines exerted on leukocytes have garnered interest in improving the efficiency of immunotherapy by increasing the infiltration of immune cells in the TME.In this study,a folic acid(FA)-modified gene delivery system based on the self-assembly of DOTAP,MPEG-PCL-MPEG,and FA-PEG-PCL-PEG-FA,namely F-PPPD,was developed to deliver plasmids encoding the immunostimulating chemokine CKb11.The delivery of plasmid CKb11(pCKb11)by F-PPPD nanoparticles resulted in the high secretion of CKb11 from tumor cells,which successfully activated T cells,suppressed the M2 polarization of macrophages,promoted the maturation of dendritic cells(DCs),facilitated the infiltration of natural killer(NK)cells and inhibited the infiltration of immunosuppressive cells in tumor tissues.Administration of F-PPPD/pCKb11 also significantly suppressed the cancer progression.Our study demonstrated a nanotechnology-enabled delivery of pCKb11,that remodeled the immunosuppressive TME,for cancer treatment.展开更多
Immunosuppression tumor microenvironment(TME)seriously impedes anti-tumor immune response,resulting in poor immunotherapy effect of cancer.This study develops a folate-modified delivery system to transport the plasmid...Immunosuppression tumor microenvironment(TME)seriously impedes anti-tumor immune response,resulting in poor immunotherapy effect of cancer.This study develops a folate-modified delivery system to transport the plasmids encoding immune stimulatory chemokine CKb11 and PD-L1 inhibitors to tumor cells,resulting in high CKb11 secretion from tumor cells,successfully activating immune cells and increasing cytokine secretion to reshape the TME,and ultimately delaying tumor progression.The chemokine CKb11 enhances the effectiveness of tumor immunotherapy by increasing the infiltration of immune cells in TME.It can cause high expression of IFN-γ,which is a double-edged sword that inhibits tumor growth while causing an increase in the expression of PD-L1 on tumor cells.Therefore,combining CKb11 with PD-L1 inhibitors can counterbalance the suppressive impact of PD-L1 on anti-cancer defense,leading to a collaborative anti-tumor outcome.Thus,utilizing nanotechnology to achieve targeted delivery of immune stimulatory chemokines and immune checkpoint inhibitors to tumor sites,thereby reshaping immunosuppressive TME for cancer treatment,has great potential as an immunogene therapy in clinical applications.展开更多
基金the Ministry of Science and Technology of the People’s Republic of China(No.2018ZX09201018)Sichuan Science and Technology Program(No.2019YFS0089,2019YFS0340 and 2020YFS0217)+4 种基金the China Postdoctoral Science Foundation(No.2020M680150)full-time postdoctoral research and development fund of Sichuan University(No.20826041D4048)the full-time postdoctoral research and development fund of West China Hospital of Sichuan University(No.2020HXBH059 and No.2020HXBH002)1·3·5 project of excellent development of discipline of West China Hospital of Sichuan University(No.ZYYC21005)the Natural Science Foundation Youth Project of Jiangsu Province(BK20190989).
文摘The immunosuppressive tumor microenvironment(TME)of cancer strongly hinders the anti-tumor immune responses,thereby resulting in disappointing responses to immunotherapy.Chemoattractive and promotive traits of chemokines exerted on leukocytes have garnered interest in improving the efficiency of immunotherapy by increasing the infiltration of immune cells in the TME.In this study,a folic acid(FA)-modified gene delivery system based on the self-assembly of DOTAP,MPEG-PCL-MPEG,and FA-PEG-PCL-PEG-FA,namely F-PPPD,was developed to deliver plasmids encoding the immunostimulating chemokine CKb11.The delivery of plasmid CKb11(pCKb11)by F-PPPD nanoparticles resulted in the high secretion of CKb11 from tumor cells,which successfully activated T cells,suppressed the M2 polarization of macrophages,promoted the maturation of dendritic cells(DCs),facilitated the infiltration of natural killer(NK)cells and inhibited the infiltration of immunosuppressive cells in tumor tissues.Administration of F-PPPD/pCKb11 also significantly suppressed the cancer progression.Our study demonstrated a nanotechnology-enabled delivery of pCKb11,that remodeled the immunosuppressive TME,for cancer treatment.
基金supported by Sichuan Science and Technology Program(No.2023YFS0170,2023NSFSC1931)supported by Medical Science and Technology Project of Sichuan Provincial Health Commission(No.21PJ009)+2 种基金supported by the National Natural Science Foundation of China(No.32222046,32371545,82103635)supported by the Technological innovation research and development project of Chengdu Science and Technology Bureau(2022-YF05-01589-SN)The 1⋅3⋅5 project of excellent development of discipline of West China Hospital of Sichuan University(No.ZYGC21022).
文摘Immunosuppression tumor microenvironment(TME)seriously impedes anti-tumor immune response,resulting in poor immunotherapy effect of cancer.This study develops a folate-modified delivery system to transport the plasmids encoding immune stimulatory chemokine CKb11 and PD-L1 inhibitors to tumor cells,resulting in high CKb11 secretion from tumor cells,successfully activating immune cells and increasing cytokine secretion to reshape the TME,and ultimately delaying tumor progression.The chemokine CKb11 enhances the effectiveness of tumor immunotherapy by increasing the infiltration of immune cells in TME.It can cause high expression of IFN-γ,which is a double-edged sword that inhibits tumor growth while causing an increase in the expression of PD-L1 on tumor cells.Therefore,combining CKb11 with PD-L1 inhibitors can counterbalance the suppressive impact of PD-L1 on anti-cancer defense,leading to a collaborative anti-tumor outcome.Thus,utilizing nanotechnology to achieve targeted delivery of immune stimulatory chemokines and immune checkpoint inhibitors to tumor sites,thereby reshaping immunosuppressive TME for cancer treatment,has great potential as an immunogene therapy in clinical applications.
