Neutrophil-integrated syncytial CAR macrophage for cancer immunotherapy
(1) Tian T (2) Zhao S (3) Tian T (4) Li W (5) Zhang Z (6) Shi T (7) Li X (8) Liu X (9) Xu H (10) Guo Y (11) Zhang B (12) Jiang W (13) Niu B (14) Zhang Z
Tian et al. fused second-generation CAR-macrophages with neutrophils, generating syncytial (S)-CAR-M with enhanced chemokine-driven solid tumor infiltration and cytotoxicity. S-CAR-Ms increased antigen presentation, generated NETs, and released ROS, killing tumor cells and enhancing phagocytosis of tumor cell debris through both scFv–antigen and PtdSer–MerTK pathways. In mice, S-CAR-Ms eliminated primary tumors and metastases, induced epitope spreading that reduced target-antigen-low cell escape, prevented recurrence, and improved survival. S-CAR-Ms also synergized with both radiotherapy and surgical resection.
Contributed by Lauren Hitchings
(1) Tian T (2) Zhao S (3) Tian T (4) Li W (5) Zhang Z (6) Shi T (7) Li X (8) Liu X (9) Xu H (10) Guo Y (11) Zhang B (12) Jiang W (13) Niu B (14) Zhang Z
Tian et al. fused second-generation CAR-macrophages with neutrophils, generating syncytial (S)-CAR-M with enhanced chemokine-driven solid tumor infiltration and cytotoxicity. S-CAR-Ms increased antigen presentation, generated NETs, and released ROS, killing tumor cells and enhancing phagocytosis of tumor cell debris through both scFv–antigen and PtdSer–MerTK pathways. In mice, S-CAR-Ms eliminated primary tumors and metastases, induced epitope spreading that reduced target-antigen-low cell escape, prevented recurrence, and improved survival. S-CAR-Ms also synergized with both radiotherapy and surgical resection.
Contributed by Lauren Hitchings
ABSTRACT: The limited effectiveness of chimeric antigen receptor macrophage (CAR-M) therapy is largely due to poor tumor infiltration, reduced effector function and immune escape of target antigen-low tumors. Here we developed syncytial CAR-Ms (S-CAR-M) by fusing CAR-Ms with neutrophils. S-CAR-Ms accumulated in tumors more than conventional CAR-Ms because of chemokine-driven migration. By releasing neutrophil extracellular traps and reactive oxygen species inherited from neutrophils, S-CAR-Ms increased PtdSer exposure on tumor cells, leading to efficient phagocytosis of tumor debris through both the scFv-antigen and PtdSer-MerTK pathways. Thus, a single dose of S-CAR-Ms can reduce tumor burden, limit metastasis and prevent tumor recurrence in syngeneic and xenograft mouse models. Additionally, S-CAR-M therapy triggered antigen spreading, minimizing escape by target antigen-low tumor cells. S-CAR-Ms overcome limitations of conventional CAR-Ms toward solid tumors.
Author Info:
(1) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. (2) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Chi
na. (3) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. (4) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. (5) Clinical Center for Biotherapy, Department of Hepatobiliary Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. Clinical Research Center for Precision Medicine of Abdominal Tumor of Fujian Province, Xiamen Key Laboratory of Biotherapy, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. (6) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. (7) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. (8) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. (9) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. (10) Department of Pharmacy, Liyuan Hospital, Huazhong University of Science and Technology, Wuhan, China. (11) Clinical Center for Biotherapy, Department of Hepatobiliary Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. Clinical Research Center for Precision Medicine of Abdominal Tumor of Fujian Province, Xiamen Key Laboratory of Biotherapy, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. (12) Clinical Research Center for Precision Medicine of Abdominal Tumor of Fujian Province, Xiamen Key Laboratory of Biotherapy, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. Central Laboratory, Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. (13) Clinical Center for Biotherapy, Department of Hepatobiliary Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. niu.boning@zsxmhospital.com. Clinical Research Center for Precision Medicine of Abdominal Tumor of Fujian Province, Xiamen Key Laboratory of Biotherapy, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. niu.boning@zsxmhospital.com. Central Laboratory, Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. niu.boning@zsxmhospital.com. (14) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. zhipingzhang@hust.edu.cn. National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, China. zhipingzhang@hust.edu.cn. Hubei Engineering Research Centre for Novel Drug Delivery System, Huazhong University of Science and Technology, Wuhan, China. zhipingzhang@hust.edu.cn.
