Li Yong, Huang Huiqin, Xie Hang, Cao Rongxiang, Li Xiuling, Huang Feijian, Lin Lu, Chen Limin
Department of Pulmonary and Critical Care Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, China.
Fujian Provincial Key Laboratory of Medical Testing, Fujian Academy Of Medical Sciences, Fuzhou, Fujian 350000, China.
Cytokine. 2025 Feb;186:156833. doi: 10.1016/j.cyto.2024.156833. Epub 2024 Dec 18.
Lung adenocarcinoma (LUAD) stands out as a prevalent malignant tumor necessitating innovative strategies to enhance therapeutic outcomes. Akkermansia muciniphila (AKK) has emerged as intricately linked to tumor immunotherapy, yet its impact on natural killer (NK) cells, which play a crucial role in immunotherapy, remains unclear. This study aims to investigate the effects of AKK outer membrane proteins on NK cells in LUAD and elucidate potential associated molecular mechanisms. 16S rRNA sequencing was employed to analyze bacterial genera and their abundance in fecal samples from LUAD patients. Co-culturing of NK-92 cells with LUAD cells, with or without treatment of AKK outer membrane protein Amuc_1100, was conducted to investigate the mechanisms of AKK on LUAD. Additionally, a xenograft mouse model was established to validate the effects of AKK in an in vivo setting. The experimental findings indicated that LUAD patients with elevated AKK levels in their fecal samples demonstrated increased NK cell infiltration and reduced TGF-β levels. Treatment with Amuc_1100 elevated TNF-α and IL-15 cytokine levels, decreased TGF-β levels and proteins associated with TGF-β pathway, enhanced NK cell cytotoxicity, upregulated perforin and granzyme B expression, induced apoptosis and cell cycle arrest, thereby inhibiting cancer cell proliferation. Amuc_1100 also impeded tumor growth in vivo. In summary, these results suggest that AKK activates NK cells to target tumor cells by suppressing the TGF-β signaling pathway in LUAD cells, underscoring the potential of Akk as an effective immunotherapeutic agent in LUAD NK cell-directed therapies.
肺腺癌（LUAD）是一种常见的恶性肿瘤，需要创新策略来提高治疗效果。嗜黏蛋白阿克曼氏菌（AKK）已被证明与肿瘤免疫治疗密切相关，但其对在免疫治疗中起关键作用的自然杀伤（NK）细胞的影响仍不清楚。本研究旨在探讨AKK外膜蛋白对LUAD中NK细胞的影响，并阐明潜在的相关分子机制。采用16S rRNA测序分析LUAD患者粪便样本中的细菌属及其丰度。将NK-92细胞与LUAD细胞共培养，分别添加或不添加AKK外膜蛋白Amuc_1100，以研究AKK对LUAD的作用机制。此外，建立了异种移植小鼠模型，以验证AKK在体内的作用效果。实验结果表明，粪便样本中AKK水平升高的LUAD患者NK细胞浸润增加，TGF-β水平降低。用Amuc_1100处理可提高TNF-α和IL-15细胞因子水平，降低TGF-β水平及与TGF-β通路相关的蛋白水平，增强NK细胞的细胞毒性，上调穿孔素和颗粒酶B的表达，诱导细胞凋亡和细胞周期停滞，从而抑制癌细胞增殖。Amuc_1100在体内也能抑制肿瘤生长。总之，这些结果表明，AKK通过抑制LUAD细胞中的TGF-β信号通路来激活NK细胞以靶向肿瘤细胞，凸显了阿克曼氏菌作为LUAD中NK细胞导向治疗的有效免疫治疗剂的潜力。
