Journal for immunotherapy of cancer · 2025
Co-expression of IL-15 and CCL21 strengthens CAR-NK cells to eliminate tumors in concert with T cells and equips them with PI3K/AKT/mTOR signal signature.
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Wang Xindi, Luo Wenjing, Chen Zhaozhao, Li Chenggong, Zhou Jie, Huang Zhongpei, Tang Lu, Wu Jianghua, Wu Zhuolin, Li Yingying, Zhang Yinqiang, Kang Yun, Liu Qiaolin, Xu Jia, Xiong Wei, Deng Jun, Mei Heng, Hu Yu
Аннотация
BACKGROUND: Chimeric antigen receptor (CAR)-natural killer (NK) cell therapy has demonstrated safety and feasibility in clinical settings; however, limited efficacy due to intrinsic dysfunction and extrinsic suppression remains an unresolved issue. T cells provide multifaceted support to NK cell-mediated responses. Here, we aimed to design a novel CD19-targeted CAR-NK, engineered with secreted interleukin-15 and C-C motif chemokine ligand 21 (ie, 15×21 CAR-NK), capable of recruiting and cooperating with T cells.
METHODS: We characterized 15×21 CAR-NK cells by performing experiments in vitro and in mouse models, and conducting RNA sequencing.
RESULTS: 15×21 CAR-NK cells exhibit strong capabilities in cytotoxicity, cytokine production, effector molecule expression, and T-cell recruitment in vitro. Cooperation with T cells promoted efficient tumor-cell elimination, alleviated mutual exhaustion phenotypes, and enhanced the expression of effector molecules/receptors. The recruitment and cooperative effects also result in effective tumor control in mouse models. In addition, 15×21 CAR-NK cells strongly enrich the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway - a key intracellular signaling cascade that is associated with enhanced downstream pro-survival signaling, anti-apoptotic ability, mitochondrial function, and cytotoxicity.
CONCLUSIONS: Our study highlights the intrinsic advantages and extrinsic T-cell cooperative benefits of 15×21 CAR-NK cells, providing a promising strategy for NK-cell-based immunotherapy.
METHODS: We characterized 15×21 CAR-NK cells by performing experiments in vitro and in mouse models, and conducting RNA sequencing.
RESULTS: 15×21 CAR-NK cells exhibit strong capabilities in cytotoxicity, cytokine production, effector molecule expression, and T-cell recruitment in vitro. Cooperation with T cells promoted efficient tumor-cell elimination, alleviated mutual exhaustion phenotypes, and enhanced the expression of effector molecules/receptors. The recruitment and cooperative effects also result in effective tumor control in mouse models. In addition, 15×21 CAR-NK cells strongly enrich the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway - a key intracellular signaling cascade that is associated with enhanced downstream pro-survival signaling, anti-apoptotic ability, mitochondrial function, and cytotoxicity.
CONCLUSIONS: Our study highlights the intrinsic advantages and extrinsic T-cell cooperative benefits of 15×21 CAR-NK cells, providing a promising strategy for NK-cell-based immunotherapy.