دورية أكاديمية
Targeting and cytotoxicity of chimeric antigen receptor T cells grafted with PD1 extramembrane domain
| العنوان: | Targeting and cytotoxicity of chimeric antigen receptor T cells grafted with PD1 extramembrane domain |
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| المؤلفون: | Ang Zhang, Shenyu Wang, Yao Sun, Yikun Zhang, Long Zhao, Yang Yang, Yijian Zhang, Lei Xu, Yangyang Lei, Jie Du, Hu Chen, Lian Duan, Mingyi He, Lintao Shi, Lei Liu, Quanjun Wang, Liangding Hu, Bin Zhang |
| المصدر: | Experimental Hematology & Oncology, Vol 12, Iss 1, Pp 1-14 (2023) |
| بيانات النشر: | BMC, 2023. |
| سنة النشر: | 2023 |
| المجموعة: | LCC:Diseases of the blood and blood-forming organs LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
| مصطلحات موضوعية: | Chimeric antigen receptor T cell, PD1, Off-target toxicity, Hinge domain, Tumor microenvironment, Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| الوصف: | Abstract Background Immunosuppression induced by programmed cell death protein 1 (PD1) presents a significant constraint on the effectiveness of chimeric antigen receptor (CAR)-T therapy. The potential of combining PD1/PDL1 (Programmed cell death 1 ligand 1) axis blockade with CAR-T cell therapy is promising. However, developing a highly efficient and minimally toxic approach requires further exploration. Our attempt to devise a novel CAR structure capable of recognizing both tumor antigens and PDL1 encountered challenges since direct targeting of PDL1 resulted in systemic adverse effects. Methods In this research, we innovatively engineered novel CARs by grafting the PD1 domain into a conventional second-generation (2G) CAR specifically targeting CD19. These CARs exist in two distinct forms: one with PD1 extramembrane domain (EMD) directly linked to a transmembrane domain (TMD), referred to as PE CAR, and the other with PD1 EMD connected to a TMD via a CD8 hinge domain (HD), known as PE8HT CAR. To evaluate their efficacy, we conducted comprehensive assessments of their cytotoxicity, cytokine release, and potential off-target effects both in vitro and in vivo using tumor models that overexpress CD19/PDL1. Results The findings of our study indicate that PE CAR demonstrates enhanced cytotoxicity and reduced cytokine release specifically towards CD19 + PDL1 + tumor cells, without off-target effects to CD19-PDL1 + tumor cells, in contrast to 2G CAR-T cells. Additionally, PE CAR showed ameliorative differentiation, exhaustion, and apoptosis phenotypes as assessed by flow cytometry, RNA-sequencing, and metabolic parameter analysis, after encountering CD19 + PDL1 + tumor cells. Conclusion Our results revealed that CAR grafted with PD1 exhibits enhanced antitumor activity with lower cytokine release and no PD1-related off-target toxicity in tumor models that overexpress CD19 and PDL1. These findings suggest that our CAR design holds the potential for effectively addressing the PD1 signal. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2162-3619 |
| العلاقة: | https://doaj.org/toc/2162-3619Test |
| DOI: | 10.1186/s40164-023-00438-7 |
| الوصول الحر: | https://doaj.org/article/a517f350263b4a659832f5975abbbfcfTest |
| رقم الانضمام: | edsdoj.517f350263b4a659832f5975abbbfcf |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 21623619 |
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| DOI: | 10.1186/s40164-023-00438-7 |