Cell Reports (Oct 2023)
Functional diversification and dynamics of CAR-T cells in patients with B-ALL
- Zongcheng Li,
- Lei Zhao,
- Yuanyuan Zhang,
- Li Zhu,
- Wei Mu,
- Tong Ge,
- Jin Jin,
- Jiaqi Tan,
- Jiali Cheng,
- Jue Wang,
- Na Wang,
- Xiaoxi Zhou,
- Liting Chen,
- Zhilin Chang,
- Chen Liu,
- Zhilei Bian,
- Bing Liu,
- Lilin Ye,
- Yu Lan,
- Liang Huang,
- Jianfeng Zhou
Affiliations
- Zongcheng Li
- State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, Institute of Hematology, Senior Department of Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China; Corresponding author
- Lei Zhao
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Yuanyuan Zhang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Li Zhu
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Wei Mu
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Tong Ge
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Jin Jin
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Jiaqi Tan
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Jiali Cheng
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Jue Wang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Na Wang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Xiaoxi Zhou
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Liting Chen
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Zhilin Chang
- State Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing 100850, China
- Chen Liu
- State Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing 100850, China
- Zhilei Bian
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, China
- Bing Liu
- State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, Institute of Hematology, Senior Department of Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China; State Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing 100850, China; Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou 510632, China; Corresponding author
- Lilin Ye
- Institute of Immunology, Third Military Medical University, Chongqing 400038, China; Corresponding author
- Yu Lan
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou 510632, China; Corresponding author
- Liang Huang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China; Corresponding author
- Jianfeng Zhou
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan 432826, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
- Journal volume & issue
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Vol. 42,
no. 10
p. 113263
Abstract
Summary: Understanding of cellular evolution and molecular programs of chimeric antigen receptor-engineered (CAR)-T cells post-infusion is pivotal for developing better treatment strategies. Here, we construct a longitudinal high-precision single-cell transcriptomic landscape of 7,578 CAR-T cells from 26 patients with B cell acute lymphoblastic leukemia (B-ALL) post-infusion. We molecularly identify eight CAR-T cell subtypes, including three cytotoxic subtypes with distinct kinetics and three dual-identity subtypes with non-T cell characteristics. Remarkably, long-term remission is coincident with the dominance of cytotoxic subtypes, while leukemia progression is correlated with the emergence of subtypes with B cell transcriptional profiles, which have dysfunctional features and might predict relapse. We further validate in vitro that the generation of B-featured CAR-T cells is induced by excessive tumor antigen stimulation or suppressed TCR signaling, while it is relieved by exogenous IL-12. Moreover, we define transcriptional hallmarks of CAR-T cell subtypes and reveal their molecular changes along computationally inferred cellular evolution in vivo. Collectively, these results decipher functional diversification and dynamics of peripheral CAR-T cells post-infusion.
