钾离子通道Kir2.1通过促进巨噬细胞炎症功能调控肿瘤生长的机制研究

肿瘤环境中免疫应答呈现出复杂而动态的变化，而免疫细胞低活化和功能抑制成为肿瘤免疫微环境的重要表现，如何扭转这种免疫低能状态成为肿瘤免疫研究的重要目的。肿瘤细胞坏死引发肿瘤微环境中钾离子浓度升高，并重塑免疫环境和免疫细胞的抗肿瘤功能成为近几年本领域最重要的发现之一，但其作用机制仍不明确。本研究前期筛选到巨噬细胞高表达的钾离子通道Kir2.1，发现巨噬细胞特异性敲除Kir2.1或其抑制剂均能显著抑制肿瘤的体内生长。进一步研究发现巨噬细胞Kir2.1的阻断能作为第二信号自发激活NLRP3炎症小体介导的Caspase-1活化和IL-1β分泌等炎症事件。此外我们将利用条件性敲除小鼠和特异性抑制剂，结合体内肿瘤模型及细胞功能与分子机制研究，深入探讨巨噬细胞Kir2.1对其炎症和抗肿瘤功能的影响，并揭示其分子机制。本研究将为肿瘤微环境中离子对免疫的调控功能提供理论依据，并为肿瘤免疫治疗提供新的分子靶点。

Immune response in tumor is complicated and dynamic. Usually, the tumor microenvironment (TME), which consists of a variety of immune cells and cytokines, remains highly immunosuppressive. In recent years, it has become the main purpose in tumor study to resolve the highly immunosuppressive environment. The apoptosis and death of cancer cells release cytosol potassium, leading to much higher extracellular potassium concentration in TME than that in serum. It has been one of the most important finding that the high extracellular potassium concentration remodeling the immune environment and the anti-tumor function of immune cells. However, the mechanism how high potassium concentration in TME mediates the immunity remains unclear. Previous work in this study finds that the inwardly rectifying potassium channel Kir2.1 is highly expressed in macrophage, and that the depletion Kir2.1 in macrophage could inhibit tumor growth remarkably in vivo. Moreover, blockade of Kir2.1 acts as a second signal for activation of caspase-1, secretion of IL-1β and other inflammatory events, which are mediated by NLRP3 inflammasome activation. In this study, how the potassium channel Kir2.1 in macrophage modulates the pro-inflammatory and anti-tumor function will be explored at both cellular level and molecular level, via conditional knock-out mice and specific inhibitor of Kir2.1. Our study would lay foundation for ion regulating immunity in theory, and provide new molecular target for immune therapy.