| Autor: |
Changyou Lin, Hong Pei, Xiaomei Yuan, Jia Xu, Mingwei Zou, Zhao Chen, Amber Fossier, Meizhu Liu, Seungah Goo, Ge Ying, Chunyi Tang, Lei Lei, Wenying Zhang, Zhenping Wang, Yue Hu, Zhihao Wang, Ying Zhao, Qidong Hu, Henry Ji, Runqiang Chen |
| Rok vydání: |
2022 |
| Popis: |
Chimeric antigen receptor (CAR)-T cells have shown potent clinical efficacy in the treatment of hematopoietic malignancies. However, much less has been achieved in solid tumors, in part due to the CAR-T cell exhaustion caused by inhibitory molecules in the tumor microenvironment. Given that PD-L1 is widely expressed in various tumor types and the PD1/PD-L1 axis plays a pivotal role in T cell exhaustion, we developed a novel platform using a single chain variable fragment (scFv) γδ-based TCR to target PD-L1 expressing tumors. We edited the TRAC locus in T cells and expressed an anti-PD-L1 scFv fused to the constant region of either the TCRδ or γ chain. We showed that the reconfigured γδ TCRs were capable of transducing signals once PD-L1 antigen was engaged by the scFv, leading to production of inflammatory cytokines, degranulation, and potent tumor killing activity both in vitro and in various xenograft solid tumor models. Surprisingly, we discovered that a new form of TCR, generated by fusing an scFv coding region to that of a single TCRγ chain, is sufficient to activate T cells and direct T cell functional activity. Moreover, in contrast to the classic TCRγδ, this new synthetic TCR appeared to transduce signals without complexing with endogenous CD3, which represents a new platform of cancer therapeutics. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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