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

Yue Huang; Mi Shao; Xinyi Teng; Xiaohui Si; Longyuan Wu; Penglei Jiang; Lianxuan Liu; Bohan Cai; Xiujian Wang; Yingli Han; Youqin Feng; Kai Liu; Zhaoru Zhang; Jiazhen Cui; Mingming Zhang; Yongxian Hu; Pengxu Qian; He Huang

doi:10.1016/j.xcrm.2024.101400

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. Epub 2024 Feb 1.

Authors

Yue Huang¹, Mi Shao¹, Xinyi Teng¹, Xiaohui Si¹, Longyuan Wu¹, Penglei Jiang², Lianxuan Liu³, Bohan Cai³, Xiujian Wang¹, Yingli Han¹, Youqin Feng¹, Kai Liu⁴, Zhaoru Zhang², Jiazhen Cui¹, Mingming Zhang¹, Yongxian Hu⁵, Pengxu Qian⁶, He Huang⁷

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.

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.

MeSH terms

Antigens, Neoplasm / metabolism
Humans
Immunotherapy, Adoptive / methods
Neoplasms*
Single-Chain Antibodies*
T-Lymphocytes

Substances

Antigens, Neoplasm
Single-Chain Antibodies