Despite the tremendous progress of chimeric antigen receptor T(CAR-T)cell therapy in hematological malignancies,their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenv...Despite the tremendous progress of chimeric antigen receptor T(CAR-T)cell therapy in hematological malignancies,their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenvironment(TME)and systemic toxicity caused by excessive cytokine release.As a key regulator of the immunosuppressive TME,TGF-βpromotes cytokine synthesis via the NF-κB pathway.Here,we coexpressed SMAD7,a suppressor of TGF-βsignaling,with a HER2-targeted CAR in engineered T cells.These novel CAR-T cells displayed high cytolytic efficacy and were resistant to TGF-β-triggered exhaustion,which enabled sustained tumoricidal capacity after continuous antigen exposure.Moreover,SMAD7 substantially reduced the production of inflammatory cytokines by antigen-primed CAR-T cells.Mechanistically,SMAD7 downregulated TGF-βreceptor I and abrogated the interplay between the TGF-βand NF-κB pathways in CAR-T cells.As a result,these CAR-T cells persistently inhibited tumor growth and promoted the survival of tumor-challenged mice regardless of the hostile tumor microenvironment caused by a high concentration of TGF-β.SMAD7 coexpression also enhanced CAR-T-cell infiltration and persistent activation in patient-derived tumor organoids.Therefore,our study demonstrated the feasibility of SMAD7 coexpression as a novel approach to improve the efficacy and safety of CAR-T-cell therapy for solid tumors.展开更多
Despite the successful use of the humanized monoclonal antibody trastuzumab(Herceptin)in the clinical treatment of human epidermal growth factor receptor 2(HER2)-overexpressing breast cancer,the frequently occurring d...Despite the successful use of the humanized monoclonal antibody trastuzumab(Herceptin)in the clinical treatment of human epidermal growth factor receptor 2(HER2)-overexpressing breast cancer,the frequently occurring drug resistance remains to be overcome.The regulatory mechanisms of trastuzumab-elicited immune response in the tumor microenvironment remain largely uncharacterized.Here,we found that the nonclassical histocompatibility antigen HLA-G desensitizes breast cancer cells to trastuzumab by binding to the natural killer(NK)cell receptor KIR2DL4.Unless engaged by HLA-G,KIR2DL4 promotes antibody-dependent cell-mediated cytotoxicity and forms a regulatory circuit with the interferon-γ(IFN-γ)production pathway,in which IFN-γ upregulates KIR2DL4 via JAK2/STAT1 signaling,and then KIR2DL4 synergizes with the Fey receptor to increase IFN-γ secretion by NK cells.Trastuzumab treatment of neoplastic and NK cells leads to aberrant cytokine production characterized by excessive tumor growth factor-β(TGF-β)and IFN-γ,which subsequently reinforce HLA-G/KIR2DL4 signaling.In addition,TGF-β and IFN-γ impair the cytotoxicity of NK cells by upregulating PD-L1 on tumor cells and PD-1 on NK cells.Blockade of HLA-G/KIR2DL4 signaling improved the vulnerability of HER2-positive breast cancer to trastuzumab treatment in vivo.These findings provide novel insights into the mechanisms underlying trastuzumab resistance and demonstrate the applicability of combined HLA-G and PD-L1/PD-1 targeting in the treatment of trastuzumab-resistant breast cancer.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)+2 种基金Shaanxi Innovative Research Team for Key Science and Technology(S2022-ZC-TD-0065)the Natural Science Foundation of Henan Province(No.222300420264)Tangdu Hospital-key research project(2022TDGS007).
文摘Despite the tremendous progress of chimeric antigen receptor T(CAR-T)cell therapy in hematological malignancies,their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenvironment(TME)and systemic toxicity caused by excessive cytokine release.As a key regulator of the immunosuppressive TME,TGF-βpromotes cytokine synthesis via the NF-κB pathway.Here,we coexpressed SMAD7,a suppressor of TGF-βsignaling,with a HER2-targeted CAR in engineered T cells.These novel CAR-T cells displayed high cytolytic efficacy and were resistant to TGF-β-triggered exhaustion,which enabled sustained tumoricidal capacity after continuous antigen exposure.Moreover,SMAD7 substantially reduced the production of inflammatory cytokines by antigen-primed CAR-T cells.Mechanistically,SMAD7 downregulated TGF-βreceptor I and abrogated the interplay between the TGF-βand NF-κB pathways in CAR-T cells.As a result,these CAR-T cells persistently inhibited tumor growth and promoted the survival of tumor-challenged mice regardless of the hostile tumor microenvironment caused by a high concentration of TGF-β.SMAD7 coexpression also enhanced CAR-T-cell infiltration and persistent activation in patient-derived tumor organoids.Therefore,our study demonstrated the feasibility of SMAD7 coexpression as a novel approach to improve the efficacy and safety of CAR-T-cell therapy for solid tumors.
基金This work was supported by the National Natural Sciences Foundation of China(Nos.81630069,81872326,and 81872303)the Natural Science Research and Development Program of Shaanxi Province(2018SF-215 and 2020SF-115)the Fundamental Research Funds for the Central Universities(szy012019083).
文摘Despite the successful use of the humanized monoclonal antibody trastuzumab(Herceptin)in the clinical treatment of human epidermal growth factor receptor 2(HER2)-overexpressing breast cancer,the frequently occurring drug resistance remains to be overcome.The regulatory mechanisms of trastuzumab-elicited immune response in the tumor microenvironment remain largely uncharacterized.Here,we found that the nonclassical histocompatibility antigen HLA-G desensitizes breast cancer cells to trastuzumab by binding to the natural killer(NK)cell receptor KIR2DL4.Unless engaged by HLA-G,KIR2DL4 promotes antibody-dependent cell-mediated cytotoxicity and forms a regulatory circuit with the interferon-γ(IFN-γ)production pathway,in which IFN-γ upregulates KIR2DL4 via JAK2/STAT1 signaling,and then KIR2DL4 synergizes with the Fey receptor to increase IFN-γ secretion by NK cells.Trastuzumab treatment of neoplastic and NK cells leads to aberrant cytokine production characterized by excessive tumor growth factor-β(TGF-β)and IFN-γ,which subsequently reinforce HLA-G/KIR2DL4 signaling.In addition,TGF-β and IFN-γ impair the cytotoxicity of NK cells by upregulating PD-L1 on tumor cells and PD-1 on NK cells.Blockade of HLA-G/KIR2DL4 signaling improved the vulnerability of HER2-positive breast cancer to trastuzumab treatment in vivo.These findings provide novel insights into the mechanisms underlying trastuzumab resistance and demonstrate the applicability of combined HLA-G and PD-L1/PD-1 targeting in the treatment of trastuzumab-resistant breast cancer.