Engineered triple inhibitory receptor resistance improves anti-tumor CAR-T cell performance via CD56

作者：Fan Zou, Lijuan Lu, Jun Liu, Baijin Xia, Wanying Zhang, Qifei Hu, Weiwei Liu, Yiwen Zhang, Yingtong Lin, Shuliang Jing, Mei Huang, Bifen Huang, Bingfeng Liu, Hui Zhang · 发表于：Nature Communications · 年份：2019 · DOI：10.1038/s41467-019-11893-4 · 被引用次数：123 · 研究领域：CAR-T cell therapy research、Advancements in Semiconductor Devices and Circuit Design、Silicon Carbide Semiconductor Technologies

The inhibitory receptors PD-1, Tim-3, and Lag-3 are highly expressed on tumor-infiltrating lymphocytes and compromise their antitumor activity. For efficient cancer immunotherapy, it is important to prevent chimeric antigen receptor T (CAR-T)-cell exhaustion. Here we downregulate these three checkpoint receptors simultaneously on CAR-T cells and that show the resulting PTL-CAR-T cells undergo epigenetic modifications and better control tumor growth. Furthermore, we unexpectedly find increased tumor infiltration by PTL-CAR-T cells and their clustering between the living and necrotic tumor tissue. Mechanistically, PTL-CAR-T cells upregulate CD56 (NCAM), which is essential for their effector function. The homophilic interaction between intercellular CD56 molecules correlates with enhanced infiltration of CAR-T cells, increased secretion of interferon-γ, and the prolonged survival of CAR-T cells. Ectopically expressed CD56 promotes CAR-T cell survival and antitumor response. Our findings demonstrate that genetic blockade of three checkpoint inhibitory receptors and the resulting high expression of CD56 on CAR-T cells enhances the inhibition of tumor growth.