SMAD7 expression in CAR-T cells improves persistence and safety for solid tumors
© 2023. The Author(s), under exclusive licence to CSI and USTC..
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-β promotes cytokine synthesis via the NF-κB pathway. Here, we coexpressed SMAD7, a suppressor of TGF-β signaling, 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-β receptor I and abrogated the interplay between the TGF-β and 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:21 |
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| Enthalten in: |
Cellular & molecular immunology - 21(2024), 3 vom: 03. März, Seite 213-226 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liang, Sixin [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.03.2024 Date Revised 02.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41423-023-01120-y |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM366678590 |
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| 520 | |a © 2023. The Author(s), under exclusive licence to CSI and USTC. | ||
| 520 | |a 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-β promotes cytokine synthesis via the NF-κB pathway. Here, we coexpressed SMAD7, a suppressor of TGF-β signaling, 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-β receptor I and abrogated the interplay between the TGF-β and 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 | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Zuo, Baile |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Jia |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yiyi |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Yujie |e verfasserin |4 aut | |
| 700 | 1 | |a Dong, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Xiaojuan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yiting |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Pengju |e verfasserin |4 aut | |
| 700 | 1 | |a Meng, Ruotong |e verfasserin |4 aut | |
| 700 | 1 | |a Jia, Lintao |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Angang |e verfasserin |4 aut | |
| 700 | 1 | |a Yan, Bo |e verfasserin |4 aut | |
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