期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：34
DOI：10.1073/pnas.2106612118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Chimeric antigen receptor (CAR)–engineered T cell therapies have shown tremendous success in the clinic, but excessive cytotoxic activity and poor control over engineered T cells limit the application of CAR-T therapies. Here we have developed resveratrol (RES)–triggered regulation devices (on/off) that could be installed into CAR-T cells, which allow precise control over T cell activity through adjustment of RES dosage. We further demonstrated RES-inducible/repressible CAR expression and reversible control over T cell activation via a RES-titratable mechanism. Our results reveal that RES
ind-CAR T cells can be dose-dependently activated by RES with strong anticancer cytotoxicity. Our RES-controlled systems establish proof of concept for strategies to control cancer immunotherapies based on the RES-regulated repression/induction of therapeutic immune cells.
Chimeric antigen receptor (CAR)–engineered T cell therapies have been recognized as powerful strategies in cancer immunotherapy; however, the clinical application of CAR-T is currently constrained by severe adverse effects in patients, caused by excessive cytotoxic activity and poor T cell control. Herein, we harnessed a dietary molecule resveratrol (RES)–responsive transactivator and a transrepressor to develop a repressible transgene expression (RES
rep) device and an inducible transgene expression (RES
ind) device, respectively. After optimization, these tools enabled the control of CAR expression and CAR-mediated antitumor function in engineered human cells. We demonstrated that a resveratrol-repressible CAR expression (RES
rep-CAR) device can effectively inhibit T cell activation upon resveratrol administration in primary T cells and a xenograft tumor mouse model. Additionally, we exhibit how a resveratrol-inducible CAR expression (RES
ind-CAR) device can achieve fine-tuned and reversible control over T cell activation via a resveratrol-titratable mechanism. Furthermore, our results revealed that the presence of RES can activate RES
ind-CAR T cells with strong anticancer cytotoxicity against cells in vitro and in vivo. Our study demonstrates the utility of RES
rep and RES
ind devices as effective tools for transgene expression and illustrates the potential of RES
rep-CAR and RES
ind-CAR devices to enhance patient safety in precision cancer immunotherapies.
