2. Academic Validation
  3. Inhibition of CD38 enzymatic activity enhances CAR-T cell immune-therapeutic efficacy by repressing glycolytic metabolism

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

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: 1313016@zju.edu.cn.
  • 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: axu@zju.edu.cn.
  • 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: huanghe@zju.edu.cn.
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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