Activating innate immune responses repolarizes hPSC-derived CAR macrophages to improve anti-tumor activity
- Cell Stem Cell. 2024 Jul 5;31(7):1003-1019.e9. doi: 10.1016/j.stem.2024.04.012.
- 1. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300020, China. Electronic address: [email protected].
- 2. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300020, China.
- 3. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300020, China; School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
- 4. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300020, China; School of Medicine, Nankai University, Tianjin 300071, China.
- 5. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300020, China; School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
- 6. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China.
- 7. School of Medicine, Sun Yat-sen University, Guangzhou 510006, China.
- 8. School of Medicine, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: [email protected].
- 9. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300020, China. Electronic address: [email protected].
- 10. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300020, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin 300020, China; Department of Stem Cell & Regenerative Medicine, Peking Union Medical College, Tianjin 300020, China. Electronic address: [email protected].
Generation of chimeric antigen receptor Macrophages (CAR-Ms) from human pluripotent stem cells (hPSCs) offers new prospects for Cancer Immunotherapy but is currently challenged by low differentiation efficiency and limited function. Here, we develop a highly efficient monolayer-based system that can produce around 6,000 Macrophages from a single hPSC within 3 weeks. Based on CAR structure screening, we generate hPSC-CAR-Ms with stable CAR expression and potent tumoricidal activity in vitro. To overcome the loss of tumoricidal activity of hPSC-CAR-Ms in vivo, we use interferon-γ and monophosphoryl lipid A to activate an innate immune response that repolarizes the hPSC-CAR-Ms to tumoricidal Macrophages. Moreover, through combined activation of T cells by hPSC-CAR-Ms, we demonstrate that activating a collaborative innate-adaptive immune response can further enhance the anti-tumor effect of hPSC-CAR-Ms in vivo. Collectively, our study provides feasible methodologies that significantly improve the production and function of hPSC-CAR-Ms to support their translation into clinical applications.