Nerves Stimulate Cross-talk Between Gastric Cancer and Group 3 Innate Lymphoid Cells to Enhance Immunosuppression

The immunosuppressive tumor microenvironment (TME) enables cancer cells to evade clinical immunotherapies. Neural networks are vital components of the TME, and interactions among cancer cells, neuronal cells, and immune cells mediate immunosuppression. Hence, understanding the mechanisms of intercellular cross-talk could inform immunomodulatory approaches to enhance immunotherapy efficacy. In this study, we found that the vagus nerve regulated the cross-talk between gastric cancer cells and group 3 innate lymphoid cells (ILC3), boosting immune resistance in gastric cancer by enhancing programmed cell death ligand 1 (PD-L1) expression. Specifically, the infiltrated vagus nerve released acetylcholine (ACh) that elevated the expression of lipase ABHD16A in gastric cancer cells, facilitating the production and secretion of the metabolite lysophosphatidylserine (LysoPS) into the TME. LysoPS facilitated the proliferation and activation of ILC3s in the TME, resulting in the production of the cytokine IL22 via the GPR34-AKT-STAT3 axis. In turn, IL22 triggered the unfolded protein response (UPR) in gastric cancer cells, which led to an increase in PD-L1 expression that enhanced immune resistance. Importantly, targeting ACh or the cross-talk between gastric cancer cells and ILC3s significantly enhanced the efficacy of anti-PD-L1 immunotherapy. Serum levels of LysoPS and IL22 were elevated in patients with gastric cancer, particularly those with perineural invasion. Collectively, these findings provide valuable insights into the cross-talk among gastric cancer cells, nerve cells, and ILC3s that regulate immunosuppression and response to anti-PD-L1 immunotherapy, emphasizing the potential clinical significance of this axis for detecting and treating gastric cancer. Significance: Vagus nerve-derived acetylcholine regulates cross-talk between gastric cancer cells and innate lymphoid cells to upregulate PD-L1 and promote immunosuppression, revealing potential therapeutic and diagnostic strategies for gastric cancer patients.