A PD-L1-targeting chimeric switch receptor enhances efficacy of CAR-T cell for pleural and peritoneal metastasis

作者：Qizhi Ma, Xia He, Benxia Zhang, Fuchun Guo, Xuejin Ou, Qiyu Yang, Pei Shu, Yue Chen, Kai Li, Ge Gao, Yajuan Zhu, Diyuan Qin, Jie Tang, Xiaoyu Li, Jing Meng, Jian Zhao, Zeming Mo, Ning Liu, Yao Zeng, Kexun Zhou, Mingyang Feng, Wei‐Ting Liao, Wanting Lei, Qiu Li, Dan Li, Yongsheng Wang · 发表于：Signal Transduction and Targeted Therapy · 年份：2022 · DOI：10.1038/s41392-022-01198-2 · 被引用次数：51 · 研究领域：CAR-T cell therapy research

Pleural and peritoneal metastasis accompanied by malignant pleural effusion (MPE) or malignant ascites (MA) is frequent in patients with advanced solid tumors that originate from the lung, breast, gastrointestinal tract and ovary. Regional delivery of CAR-T cells represents a new strategy to control tumor dissemination in serous cavities. However, malignant effusions constitute an immune-suppressive environment that potentially induces CAR-T cell dysfunction. Here, we demonstrated that the anti-tumor cytotoxicity of conventional 2nd-generation CAR-T cells was significantly inhibited by both the cellular and non-cellular components of MPE/MA, which was primarily attributed to impaired CAR-T cell proliferation and cytokine production in MPE/MA environment. Interestingly, we found that PD-L1 was widely expressed on freshly-isolated MPE/MA cells. Based on this feature, a novel PD-L1-targeting chimeric switch receptor (PD-L1.BB CSR) was designed, which can bind to PD-L1, switching the inhibitory signal into an additional 4-1BB signal. When co-expressed with a 2nd-generation CAR, PD-L1.BB CSR-modified CAR-T cells displayed superior fitness and enhanced functions in both culture medium and MPE/MA environment, causing rapid and durable eradication of pleural and peritoneal metastatic tumors in xenograft models. Further investigations revealed elevated expressions of T-cell activation, proliferation, and cytotoxicity-related genes, and we confirmed that PD-L1 scFv and 4-1BB intracellu...