Abstract
Chimeric antigen receptor T cell (CAR-T) 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 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.
Overview
- The study investigates the role of nitric oxide (NO) in chimeric antigen receptor T cell (CAR-T) therapy for refractory or relapsed lymphoma and leukemia patients. The study aims to understand the impact of NO on CAR-T cell persistence and anti-tumor efficacy, and to identify potential solutions to combat NO stress and improve CAR-T therapy outcomes. The methodology used includes in vitro experiments with CAR-T cells and a mouse tumor model, as well as analysis of mitochondrial dynamics and T-cell activation markers. The primary objective of the study is to identify the mechanisms underlying NO-induced impairment of CAR-T cell persistence and functionality, and to develop strategies to enhance CAR-T cell expansion and anti-tumor capacity.
Comparative Analysis & Findings
- The study found that continuous signaling from CAR promotes excessive NO production, which in turn suppresses S-nitrosoglutathione reductase (GSNOR) expression in T cells. This leads to increased protein S-nitrosylation, resulting in impaired mitochondrial fitness and deficiency of T cell stemness. Enforced expression of GSNOR promotes memory differentiation of CAR-T cells, rendering them better resistance to mitochondrial dysfunction and enhancing their expansion and anti-tumor capacity in vitro and in a mouse tumor model. These findings suggest that NO stress plays a critical role in restricting CAR-T cell persistence and functionality, and that GSNOR overexpression may provide a solution to combat NO stress and improve CAR-T therapy outcomes.
Implications and Future Directions
- The study's findings have significant implications for the development of CAR-T therapy for refractory or relapsed lymphoma and leukemia patients. The study identifies a critical role of NO in restricting CAR-T cell persistence and functionality, and suggests that GSNOR overexpression may provide a solution to combat NO stress and improve CAR-T therapy outcomes. Future research directions could include further investigation of the mechanisms underlying NO-induced impairment of CAR-T cell persistence and functionality, as well as development of novel strategies to enhance CAR-T cell expansion and anti-tumor capacity in vivo. The study's findings could also have broader implications for the development of other T-cell-based therapies, as NO stress is known to play a role in T-cell activation and function.