GSNOR overexpression enhances CAR-T cell stemness and anti-tumor function by enforcing mitochondrial fitness

作者：Qing Niu, Haixiao Zhang, Fang Wang, Xing Xu, Yuechen Luo, Baolin He, Mingxia Shi, Erlie Jiang, Xiaoming Feng · 发表于：Molecular Therapy · 年份：2024 · DOI：10.1016/j.ymthe.2024.03.033 · 被引用次数：10 · 研究领域：CAR-T cell therapy research、Viral Infectious Diseases and Gene Expression in Insects、Virus-based gene therapy research

Chimeric antigen receptor-T (CAR-T) cell has been developed as a promising agent for patients with refractory or relapsed lymphoma and leukemia, but not all the recipients could achieve a long-lasting remission. The limited capacity of in vivo expansion and memory differentiation post activation is one of the major reasons for suboptimal CAR-T therapeutic efficiency. Nitric oxide (NO) plays multifaceted roles in mitochondrial dynamics and T cell activation, but its function on CAR-T cell persistence and anti-tumor efficacy remains unknown. Herein, we found the continuous signaling from CAR not only promotes excessive NO production, but also suppressed S-nitrosoglutathione reductase (GSNOR) expression in T cells, which collectively led to increased protein S-nitrosylation, resulting in impaired mitochondrial fitness and deficiency of T cell stemness. Intriguingly, enforced expression of GSNOR promoted memory differentiation of CAR-T cell after immune activation, rendered CAR-T better resistance to mitochondrial dysfunction, further enhanced CAR-T cell expansion and anti-tumor capacity in vitro and in a mouse tumor model. Thus, we revealed a critical role of NO in restricting CAR-T cell persistence and functionality, and defined that GSNOR overexpression may provide a solution to combat NO stress and render patients with more durable protection from CAR-T therapy.