Wu Yi-Ying, Chen Ming-Shan, Chen I-Chun, Wu Feng-Hsu, Liao Tsai-Ling, Wen Hsiao-Wei, Nielsen Brent L, Liu Hung-Jen
Institute of Molecular Biology, National Chung Hsing University, Taichung 402, Taiwan.
The iEGG and Animal Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan.
Int J Mol Sci. 2025 Mar 31;26(7):3236. doi: 10.3390/ijms26073236.
Lidocaine, a local anesthetic, has been shown to modulate immune responses. This study examines its effects on cytokine production in peripheral blood mononuclear cells (PBMCs) from healthy donors and tumor-infiltrating immune cells (TIICs) from gastric cancer patients. PBMCs from healthy donors and TIICs from gastric cancer patients were treated with lidocaine. Cytokine production was assessed using flow cytometry and cytokine assays, with a focus on IFN-γ, IL-12, IL-10, TGF-β, and IL-35 levels. Cytotoxicity against primary gastric cancer cells (PGCCs) was also evaluated. Lidocaine inhibited IFN-γ production in CD8 PBMCs and IL-12 in CD14 PBMCs while increasing anti-inflammatory cytokines (IL-10, TGF-β, IL-35) in CD4CD25 and CD14 cells. In TIICs, lidocaine enhanced IFN-γ and IL-12 production in CD8 and CD14 cells while reducing IL-10, TGF-β, and IL-35 levels, promoting an M1-like phenotype in macrophages. Mechanistically, lidocaine enhanced IFN-γ production in sorted CD8 TIICs through G-protein-coupled receptor (GPCR) signaling and increased IL-12 production in sorted CD14 TIICs via the toll-like receptor 4 (TLR4) signaling pathway. Lidocaine also increased IFN-γ production and cytotoxicity in CD8 TIICs via NF-κB activation. Importantly, lidocaine did not affect the viability of PBMCs, TIICs, or PGCCs at concentrations up to 1.5 mM. Lidocaine reprogrammed the tumor immune microenvironment, enhancing anti-tumor immune responses, suggesting its potential to modulate immune functions in gastric cancer.
利多卡因是一种局部麻醉剂，已被证明可调节免疫反应。本研究考察了其对健康供体外周血单核细胞（PBMC）以及胃癌患者肿瘤浸润免疫细胞（TIIC）中细胞因子产生的影响。对健康供体的PBMC和胃癌患者的TIIC进行利多卡因处理。使用流式细胞术和细胞因子检测法评估细胞因子的产生，重点关注IFN-γ、IL-12、IL-10、TGF-β和IL-35的水平。还评估了对原发性胃癌细胞（PGCC）的细胞毒性。利多卡因抑制CD8 PBMC中IFN-γ的产生以及CD14 PBMC中IL-12的产生，同时增加CD4CD25和CD14细胞中抗炎细胞因子（IL-10、TGF-β、IL-35）的水平。在TIIC中，利多卡因增强CD8和CD14细胞中IFN-γ和IL-12的产生，同时降低IL-10、TGF-β和IL-35水平，促进巨噬细胞呈现M1样表型。从机制上讲，利多卡因通过G蛋白偶联受体（GPCR）信号传导增强分选的CD8 TIIC中IFN-γ的产生，并通过Toll样受体4（TLR4）信号通路增加分选的CD14 TIIC中IL-12的产生。利多卡因还通过NF-κB激活增加CD8 TIIC中IFN-γ的产生和细胞毒性。重要的是，在浓度高达1.5 mM时，利多卡因不影响PBMC、TIIC或PGCC的活力。利多卡因重塑了肿瘤免疫微环境，增强了抗肿瘤免疫反应，表明其在胃癌中调节免疫功能的潜力。
