Across various CAR T cell models, Huang et al. found that CD38 activity played a key role in CAR T cell overactivation and exhaustion by simultaneously supporting CD38–cADPR–Ca2+ signaling (which increases NFAT activity) and limiting CD38–NAD+–SIRT1 signaling (which increases acetylated HIF1α), both of which support increased glycolysis. Chemical or genetic inhibition of CD38 enzyme activity boosted CAR T cell cytotoxicity and antitumor efficacy by reversing these effects and inhibiting glycolysis. CD38 inhibition also supported CAR T cell persistence, long-term functionality, and early differentiation towards a memory-like phenotype.
Contributed by Lauren Hitchings
ABSTRACT: Chimeric antigen receptor (CAR)-T therapy has shown superior efficacy against hematopoietic malignancies. However, many patients failed to achieve sustainable tumor control partially due to CAR-T cell exhaustion and limited persistence. In this study, by performing single-cell multi-omics data analysis on patient-derived CAR-T cells, we identify CD38 as a potential hallmark of exhausted CAR-T cells, which is positively correlated with exhaustion-related transcription factors and further confirmed with in vitro exhaustion models. Moreover, inhibiting CD38 activity reverses tonic signaling- or tumor antigen-induced exhaustion independent of single-chain variable fragment design or costimulatory domain, resulting in improved CAR-T cell cytotoxicity and antitumor response. Mechanistically, CD38 inhibition synergizes the downregulation of CD38-cADPR -Ca(2+) signaling and activation of the CD38-NAD(+)-SIRT1 axis to suppress glycolysis. Collectively, our findings shed light on the role of CD38 in CAR-T cell exhaustion and suggest potential clinical applications of CD38 inhibition in enhancing the efficacy and persistence of CAR-T cell therapy.
Author Info: (1) Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Han
Author Info: (1) Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China. (2) Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China. (3) Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China. (4) Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China. (5) Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China. (6) Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China; Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou 310058, China. (7) Institute of Hematology, Zhejiang University, Hangzhou 310058, China. (8) Institute of Hematology, Zhejiang University, Hangzhou 310058, China. (9) Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China. (10) Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China. (11) Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China. (12) Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China. (13) Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China; Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou 310058, China. (14) Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China. (15) Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China. (16) Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China. Electronic address: 1313016@zju.edu.cn. (17) Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China; Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou 310058, China. Electronic address: axu@zju.edu.cn. (18) Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China. Electronic address: huanghe@zju.edu.cn.
