ABSTRACT:Although radiotherapy(RT)can induce immunogenic cell death(ICD),the endogenous resistance of tumor cells to X-rays and the immunosuppressive microenvironment has suppressed its therapeutic effect,which can ea...ABSTRACT:Although radiotherapy(RT)can induce immunogenic cell death(ICD),the endogenous resistance of tumor cells to X-rays and the immunosuppressive microenvironment has suppressed its therapeutic effect,which can easily lead to tumor recurrence and metastasis after RT.Herein,we prepared a glutathione(GSH)-responsive system called AHD,by loading Aurora-A inhibitor alisertib(Ali)and iron protoporphyrin Ⅸ chloride(Hemin),for X-raytriggered continuous reactive oxygen species(ROS)generation to sensitize breast cancer senescence immunotherapy.AHD accumulates at the tumor tissue through the enhanced permeability and retention(EPR)effect,shows high specificity for the tumor microenvironment with overexpressed GSH,and rapidly releases Ali and Hemin.Under external X-ray irradiation,tumor cells produce H_(2)O_(2),and AHD activates Hemin to catalyze the chemical kinetics process of H_(2)O_(2),continuously generating hydroxyl radicals(·OH).Meanwhile,AHD can also induce tumor cell senescence by up-regulating P21 and P16 expressions.In vitro and in vivo experimental results show that the cascade ROS generation induced by the AHD system can trigger extensive ICD in tumor cells,alleviate the immunosuppressive microenvironment after RT,activate the anti-tumor immune ability of CD8^(+)T cells.Therefore,AHD can be used as a tumor immunomodulator to enhance radioimmunotherapy and has great potential for clinical translation.展开更多
Glioma is an aggressive brain tumor with a poor prognosis.Establishing an in vitro culture model that closely replicates the cellular composition and microenvironment of the original tumor has been challenging,limitin...Glioma is an aggressive brain tumor with a poor prognosis.Establishing an in vitro culture model that closely replicates the cellular composition and microenvironment of the original tumor has been challenging,limiting its clinical applications.Here,we present a novel approach to generate glioma organoids with a microenvironment(GlioME)from patient-derived glioma tissue.These organoids maintain the genetic and epigenetic characteristics of the primary tumor and preserve cell-to-cell interactions within the tumor microenvironment,including resident immune cells.Bulk RNA sequencing,whole exome sequencing,and DNA methylation analysis were used to confirm the molecular similarities between the organoids and primary glioma tissues.Immunofluorescence and flow cytometry were used to assess immune cell viability,comparing GlioME with floating glioma organoids.展开更多
基金financial support from the Key Laboratory of Birth Defects and Stem Cell Biobank of Guangxi(No.GXWCHZDKF-2023-09).
文摘ABSTRACT:Although radiotherapy(RT)can induce immunogenic cell death(ICD),the endogenous resistance of tumor cells to X-rays and the immunosuppressive microenvironment has suppressed its therapeutic effect,which can easily lead to tumor recurrence and metastasis after RT.Herein,we prepared a glutathione(GSH)-responsive system called AHD,by loading Aurora-A inhibitor alisertib(Ali)and iron protoporphyrin Ⅸ chloride(Hemin),for X-raytriggered continuous reactive oxygen species(ROS)generation to sensitize breast cancer senescence immunotherapy.AHD accumulates at the tumor tissue through the enhanced permeability and retention(EPR)effect,shows high specificity for the tumor microenvironment with overexpressed GSH,and rapidly releases Ali and Hemin.Under external X-ray irradiation,tumor cells produce H_(2)O_(2),and AHD activates Hemin to catalyze the chemical kinetics process of H_(2)O_(2),continuously generating hydroxyl radicals(·OH).Meanwhile,AHD can also induce tumor cell senescence by up-regulating P21 and P16 expressions.In vitro and in vivo experimental results show that the cascade ROS generation induced by the AHD system can trigger extensive ICD in tumor cells,alleviate the immunosuppressive microenvironment after RT,activate the anti-tumor immune ability of CD8^(+)T cells.Therefore,AHD can be used as a tumor immunomodulator to enhance radioimmunotherapy and has great potential for clinical translation.
基金The dataset,including bulk RNA-seq(HRA010105)whole-exome sequencing(HRA010141)+1 种基金DNA methylation sequencing(OMIX008701)has been deposited in the Genome Sequence Archive[41]in the National Genomics Data Center[42],China National Center for Bioinformation/Beijing Institute of Genomics,Chinese Academy of Sciences(PRJCA035075)。
文摘Glioma is an aggressive brain tumor with a poor prognosis.Establishing an in vitro culture model that closely replicates the cellular composition and microenvironment of the original tumor has been challenging,limiting its clinical applications.Here,we present a novel approach to generate glioma organoids with a microenvironment(GlioME)from patient-derived glioma tissue.These organoids maintain the genetic and epigenetic characteristics of the primary tumor and preserve cell-to-cell interactions within the tumor microenvironment,including resident immune cells.Bulk RNA sequencing,whole exome sequencing,and DNA methylation analysis were used to confirm the molecular similarities between the organoids and primary glioma tissues.Immunofluorescence and flow cytometry were used to assess immune cell viability,comparing GlioME with floating glioma organoids.
