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
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.
