Tandem CAR-T cells targeting FOLR1 and MSLN enhance the antitumor effects in ovarian cancer
Autor: | Rui Huang, Chen Xu, Jiao Dong, Jia-Kui Ren, Wen-Ting Wang, Zhen Liang, Feng-Jie Li, Dan Wang, Yanzhou Wang, Jie Lei, Ze-Yu Yang, Zhiqing Liang, Si-Di Li, Neng Yang |
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Rok vydání: | 2021 |
Předmět: |
Cell Survival
T cell MSLN Cell- and Tissue-Based Therapy Mice Nude Applied Microbiology and Biotechnology Cell therapy Mice Antigen Cell Line Tumor Databases Genetic medicine Animals Humans Folate Receptor 1 Mesothelin Molecular Biology Ecology Evolution Behavior and Systematics Cell Proliferation Ovarian Neoplasms biology Chemistry Cell Biology CAR-T therapy medicine.disease Interleukin-12 Xenograft Model Antitumor Assays Tumor antigen Up-Regulation Gene Expression Regulation Neoplastic ovarian cancer medicine.anatomical_structure FOLR1 IL-12 Cancer research Interleukin 12 biology.protein Cytokines Female Folate receptor 1 Transcriptome Ovarian cancer human activities Research Paper Developmental Biology |
Zdroj: | International Journal of Biological Sciences |
ISSN: | 1449-2288 |
Popis: | Given the heterogeneity of solid tumors, single-target CAR-T cell therapy often leads to recurrence, especially in ovarian cancer (OV). Here, we constructed a Tandem-CAR targeting two antigens with secretory activity (IL-12) to improve the effects of CAR-T cell therapy. Twenty coexpressed upregulated genes were identified from the GEO database, and we found FOLR1 (folate receptor 1) and MSLN (mesothelin) were specifically and highly expressed in cancer tissues and only 11.25% of samples were negative for both antigens. We observed an increased proliferation rate for these three CAR-T cells, and Tandem CAR-T cells could efficiently lyse antigen-positive OV cells in vitro and secrete higher levels of cytokines than single-target CAR-T cells. More importantly, in vivo experiments indicated that Tandem CAR-T cells markedly decreased tumor volume, exhibited enhanced antitumor activity, and prolonged mouse survival. Furthermore, the infiltration and persistence of T cells in the Tandem-CAR group were higher than those in the MSLN-CAR and Control-T groups but comparable to those in the FOLR1-CAR group. Collectively, this study demonstrated that Tandem CAR-T cells secreting IL-12 could enhance immunotherapeutic effects by reducing tumor antigen escape and increasing T cell functionality, which could be a promising therapeutic strategy for OV and other solid tumors. |
Databáze: | OpenAIRE |
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