Modified CAR T cells targeting membrane-proximal epitope of mesothelin enhances the antitumor function against large solid tumor
| Autor: | Wang Chao, Linfang Li, Liu Xiangzhen, Zhang Zhiwei, Qijun Qian, Huajun Jin, Li He, Wenxia Qin, Yang Huan, Jiang Duqing, He Zhou, Hai Xu, Li Yang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Cancer Research
medicine.medical_treatment Blotting Western Immunology Cancer immunotherapy GPI-Linked Proteins Real-Time Polymerase Chain Reaction Immunotherapy Adoptive Epitope Article Cell Line Interferon-gamma Mice Cellular and Molecular Neuroscience Antigen Cell Line Tumor medicine Animals Humans Mesothelin lcsh:QH573-671 Ovarian Neoplasms biology Tumor Necrosis Factor-alpha Chemistry lcsh:Cytology Correction Cell Biology Immunotherapy Flow Cytometry Immunohistochemistry Chimeric antigen receptor Cell culture Cancer cell Drug delivery biology.protein Cancer research Interleukin-2 Female Immunization human activities |
| Zdroj: | Cell Death and Disease, Vol 10, Iss 7, Pp 1-12 (2019) Cell Death & Disease |
| ISSN: | 2041-4889 |
| DOI: | 10.1038/s41419-019-1711-1 |
| Popis: | Mesothelin (MSLN) is an attractive antigen for chimeric antigen receptor (CAR) T therapy and the epitope selection within MSLN is essential. In this study, we constructed two types of CARs targeting either region I of MSLN (meso1 CAR, also known as a membrane-distal region) or region III of MSLN (meso3 CAR, also known as a membrane-proximal region) using a modified piggyBac transposon system. We reported that, compared with meso1 CAR T cells, meso3 CAR T cells express higher levels of CD107α upon activation and produce increased levels of interleukin-2, TNF-α, and IFN-γ against multiple MSLN-expressing cancer cells in vitro. In a real-time cell analyzer system and a three-dimensional spheroid cancer cell model, we also demonstrated that meso3 CAR T cells display an enhanced killing effect compared with that of meso1 CAR T cells. More importantly, in a gastric cancer NSG mice model, meso3 CAR T cells mediated stronger antitumor responses than meso1 CAR T cells did. We further identified that meso3 CAR T cells can effectively inhibit the growth of large ovarian tumors in vivo. Collectively, our study provides evidences that meso3 CAR T-cell therapy performs as a better immunotherapy than meso1 CAR T-cell therapy in treating MSLN-positive solid tumors. |
| Databáze: | OpenAIRE |
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