The ability to control mammalian cells such that they self-organize or enact therapeutic effects as desired has incredible implications.Not only would it further our understanding of native processes such as developme...The ability to control mammalian cells such that they self-organize or enact therapeutic effects as desired has incredible implications.Not only would it further our understanding of native processes such as development and the immune response,but it would also have powerful applications in medical fields such as regenerative medicine and immunotherapy.This control is typically obtained by synthetic circuits that use synthetic receptors,but control remains incomplete.The synthetic juxtacrine receptors(SJRs)are widely used as they are fully modular and enable spatial control,but they have limited gene expression amplification and temporal control.As these are integral facets to cell control,I therefore designed transcription factor based amplifiers that amplify gene expression and enable unidirectional temporal control by prolonging duration of target gene expression.Using a validated in silico framework for SJR signaling,I combined these amplifiers with SJRs and show that these SJR amplifier circuits can direct spatiotemporal patterning and improve the quality of self-organization.I then show that these circuits can improve chimeric antigen receptor(CAR)T cell tumor killing against various heterogenous antigen expression tumors.These amplifiers are flexible tools that improve control over SJR based circuits with both basic and therapeutic applications.展开更多
Although major progress has been made in the use of chimeric antigen receptor(CAR)-T-cell therapy for hematological malignancies,this method is ineffective against solid tumors largely because of the limited infiltrat...Although major progress has been made in the use of chimeric antigen receptor(CAR)-T-cell therapy for hematological malignancies,this method is ineffective against solid tumors largely because of the limited infiltration,activation and proliferation of CAR-T cells.To overcome this issue,we engineered CAR-T cells with synthetic Notch(synNotch)receptors,which induce local tumor-specific secretion of extracellular matrix(ECM)-degrading enzymes at the tumor site.SynNotch CAR-T cells achieve precise ECM recognition and robustly kill targeted tumors,with synNotch-induced enzyme production enabling the degradation of components of the tumor ECM.In addition,this regulation strongly increased the infiltration of CAR-T cells and the clearance of solid tumors,resulting in tumor regression without toxicity in vivo.Notably,synNotch CAR-T cells also promoted the persistent activation of CAR-T cells in patient-derived tumor organoids.Thus,we constructed a synthetic T-cell system that increases the infiltration and antitumor function of CAR-T cells,providing a strategy for targeting ECM-rich solid tumors.展开更多
文摘The ability to control mammalian cells such that they self-organize or enact therapeutic effects as desired has incredible implications.Not only would it further our understanding of native processes such as development and the immune response,but it would also have powerful applications in medical fields such as regenerative medicine and immunotherapy.This control is typically obtained by synthetic circuits that use synthetic receptors,but control remains incomplete.The synthetic juxtacrine receptors(SJRs)are widely used as they are fully modular and enable spatial control,but they have limited gene expression amplification and temporal control.As these are integral facets to cell control,I therefore designed transcription factor based amplifiers that amplify gene expression and enable unidirectional temporal control by prolonging duration of target gene expression.Using a validated in silico framework for SJR signaling,I combined these amplifiers with SJRs and show that these SJR amplifier circuits can direct spatiotemporal patterning and improve the quality of self-organization.I then show that these circuits can improve chimeric antigen receptor(CAR)T cell tumor killing against various heterogenous antigen expression tumors.These amplifiers are flexible tools that improve control over SJR based circuits with both basic and therapeutic applications.
基金supported by a grant from the National Natural Science Foundation of China(No.81972870)the Independent Research Topic of State Key Laboratory of Cancer Biology of Fourth Military Medical University(CBSKL2022ZZ20)Tangdu Hospital-key research project(2022TDGS007).
文摘Although major progress has been made in the use of chimeric antigen receptor(CAR)-T-cell therapy for hematological malignancies,this method is ineffective against solid tumors largely because of the limited infiltration,activation and proliferation of CAR-T cells.To overcome this issue,we engineered CAR-T cells with synthetic Notch(synNotch)receptors,which induce local tumor-specific secretion of extracellular matrix(ECM)-degrading enzymes at the tumor site.SynNotch CAR-T cells achieve precise ECM recognition and robustly kill targeted tumors,with synNotch-induced enzyme production enabling the degradation of components of the tumor ECM.In addition,this regulation strongly increased the infiltration of CAR-T cells and the clearance of solid tumors,resulting in tumor regression without toxicity in vivo.Notably,synNotch CAR-T cells also promoted the persistent activation of CAR-T cells in patient-derived tumor organoids.Thus,we constructed a synthetic T-cell system that increases the infiltration and antitumor function of CAR-T cells,providing a strategy for targeting ECM-rich solid tumors.
