Chimeric cytokine receptor TGF-β RⅡ/IL-21R improves CAR-NK cell function by reversing the immunosuppressive tumor microenvironment of gastric cancer
Yaojun Ren, Min Xue, Xinhui Hui, Xiuyu Liu, Muhammad Asad Farooq, Yiran Chen, Yuzhou Ji, Yixin Duan, Iqra Ajmal, Jie Yao, Wenzheng Jiang
Abstract
Gastric cancer remains a significant global health burden, characterized by regional variations in incidence and poor survival prospects in advanced stages. Natural killer (NK) cells play a crucial role in the body’s anti-cancer defense, and chimeric antigen receptor (CAR)–NK cell therapy is gaining attention as a cutting-edge and promising treatment method. This study aims to tackle the challenge of TGF-β-mediated tumor immune evasion within the immunosuppressive tumor microenvironment by designing a novel chimeric cytokine receptor TRII/21 R, which consists of extracellular domains of TGF-β receptor II (TRII) and transmembrane and intracellular domains of IL-21 receptor (21 R) and can convert the immunosuppressive signal from TGF-β in the tumor microenvironment (TME) into an NK cell activation signal through the IL-21R-STAT3 pathway. We successfully constructed NKG2D-CAR-NK cells expressing TRII/21 R and demonstrated strong anti-tumor activity against cancer cells both in vitro and in vivo. The co-expression of TRII/21 R in CAR-NK cells enhanced the cytotoxicity, promoted proliferation and survival capabilities, and reduced the expression of exhaustion markers. In the xenograft mouse model, TRII/21R-CAR-NK cells significantly inhibited tumor growth and improved the survival rate of tumor-bearing mice compared to the mice receiving control CAR-NK cells. Additionally, TRII/21 R co-expression enhanced NK cells' infiltration, activation, and persistence within the tumor, indicating a robust anti-tumor response mediated by the JAK-STAT3 signaling pathway. This study underscores the therapeutic potential of TRII/21R-modified CAR-NK cells as a breakthrough strategy for combating cancer. • NKG2D is a potential immunotherapy target for gastric cancer. • Chimeric cytokine receptor TRII/21 R binds TGF-β via extracellular domain of TGF-β receptor Ⅱ. • TRII/21 R inverts inhibitory TGF-β signal into activated IL-21 signaling and promotes CAR-NK cell effector functions. • TRII/21 R enhances antitumor efficacy and persistence of CAR-NK cells in vivo.