Norepinephrine inhibits CD8+ T cell infiltration and function, inducing anti-PD-1 mAb resistance in lung adenocarcinoma

BACKGROUND:Mental stress-induced neurotransmitters can affect the immune system in various ways, leading to tumor immune escape. Therefore, a better understanding of the potential functions of neurotransmitters in the tumor immune microenvironment is expected to promote the development of novel anti-tumor therapies, while facilitating synergistic immune therapy. METHODS: In this study, we analyzed the plasma levels of neurotransmitters in anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb)-resistance patients and sensitive patients, to identify significantly different neurotransmitters. Subsequently, animal experiments, transcriptome analysis, metabolomic analysis, and experiments in vitro were used to reveal the specific mechanism of norepinephrine’s (NE) effect on immunotherapy. RESULTS: The plasma NE levels were higher in anti-PD-1 mAb-resistance patients, which may be the main cause of anti-PD-1 mAb resistance. An animal model was established for verification, which further demonstrated that NE could cause anti-PD-1 mAb resistance. Then, from the perspective of the immunosuppressive microenvironment to explore the specific mechanism of NE-induced anti-PD-1 mAb resistance, we found that NE can affect the secretion of the C-X-C Motif Chemokine Ligand 9 (CXCL9) and the immunosuppressive metabolite adenosine (ADO) in tumor cells, thereby inhibiting chemotaxis and function of CD8+ T cells. Notably, the WNT7A/β-catenin signaling pathway plays a crucial role in the NE-induced decrease in the secretion of CXCL9 and disturbance of ADO metabolism. CONCLUSION: NE can affect the secretion of CXCL9 and ADO in tumor cells, thereby inhibiting chemotaxis and the function of CD8+ T cells and inducing anti-PD-1 mAb resistance in lung adenocarcinoma (LUAD). To explore whether ADO affects immune cell function, we treated PBMCs with 30 uM ADO for 24 h, which were subjected to transcriptome sequencing. In order to further study the mechanism of NE-induced changes of CXCL9 and ADO secretion in tumor cells, we used transcriptome sequencing to detect gene expression levels in A549 cells after NE stimulation.