Inhibition of CD38 enzymatic activity enhances CAR-T cell immune-therapeutic efficacy by repressing glycolytic metabolism

  • Cell Rep Med. 2024 Feb 20;5(2):101400. doi: 10.1016/j.xcrm.2024.101400.
Yue Huang  1 ,  Mi Shao  1 ,  Xinyi Teng  1 ,  Xiaohui Si  1 ,  Longyuan Wu  1 ,  Penglei Jiang  2 ,  Lianxuan Liu  3 ,  Bohan Cai  3 ,  Xiujian Wang  1 ,  Yingli Han  1 ,  Youqin Feng  1 ,  Kai Liu  4 ,  Zhaoru Zhang  2 ,  Jiazhen Cui  1 ,  Mingming Zhang  1 ,  Yongxian Hu  5 ,  Pengxu Qian  6 ,  He Huang  7
Affiliations
  • 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. 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.
  • 3. Institute of Hematology, Zhejiang University, Hangzhou 310058, China.
  • 4. 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. Electronic address: [email protected].
  • 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. Electronic address: [email protected].
  • 7. 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: [email protected].
PMID: 38307031 DOI: 10.1016/j.xcrm.2024.101400
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 -Ca2+ 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.

Keywords
CAR-T; CD38; SIRT1; cADPR; chimeric antigen receptor T; exhaustion; glycolysis.
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