Resilient CD8 +T cells maintain a high cytotoxic capacity by balancing ROS and energy needs via ME1 upregulation

Abstract Cytotoxic T lymphocytes (CTL) are indispensable in anti-tumor immunity. Although CTLs prone to exhaustion patients with advanced cancer, cell resiliency explains the presence of tumor-reactive that less exhausted, capable cytolytic function, expansion, and rebound response immunotherapy reject metastatic malignancies. However, features resilient cells have not been clearly defined. In this report, we demonstrate peripheral CX3CR1 +CD8 +T low mitochondrial membrane potential rebounded CTL function quickly after radiation therapy large tumor burden portraying their functional resiliency. Furthermore, low, but high, highly cytotoxic, accumulate reactive oxygen species (ROS), express more Malic enzyme 1 (ME1). ME1 overexpression increases ATP production a glycolysis-independent manner while concurrently curtailing excessive ROS activated CD8 cells; expands +NKG7 +effector enhanced cytotoxicity. Importantly, transfection mRNA promotes tumoricidal activity from cancers. Our study reveals mechanism used by balance via maintain metabolic Modification expression may be novel method improve efficacy cancer preventing exhaustion. Supported grants Mayo Clinic Foundation NIH (R01CA 256927-2)