口腔癌前微环境中T细胞浸润增加是其免疫失衡显著特征，但T细胞浸润在癌前病损恶性转化中的具体作用机制仍不明确。申请人近期发现：口腔黏膜恶性转化中，IL-1β通过上调口腔癌前微环境趋化因子而促进上皮恶性转化，提示：IL-1β介导免疫失衡可能是其促进癌前病损恶变重要方式。预实验表明：IL-1β上调FoxP3表达，且在口腔黏膜恶性转化中，Treg关键效应分子TGF-β和T Effector 效应分子IFN-γ表达呈现紊乱状态。据此，我们提出科学假说：口腔癌前微环境中，IL-1β通过介导Treg/ T Effector免疫失衡诱导上皮恶性转化。为此，项目将利用体外培养和大鼠诱癌模型深入阐述干预IL-1β是否并如何影响Treg/T Effector免疫平衡从而促进口腔癌前病损转化，并在临床标本中验证其与口腔癌前病损转化的相关性；为深入揭示炎症促进口腔癌前损害发展新机制、发现口腔癌防治新靶点提供基础。

Accumulating evidence has suggested that immune imbalance is actively engaged in the oral mucosal epithelia malignant transformation, which is characterized by infiltration of large amounts of T cells. However, the exact mechanisms in which T cells mediate immune imbalance in inflammatory microenvironment capable of promoting the malignant transformation remain unknown. We have recently demonstrated that interleukin1 beta (IL-1β) played a significant role in oral epithelia malignant transformation by up-regulating expressions of several chemokine genes and participated in the regulation of immune homeostasis during epithelia malignant transformation. Our pilot experiments also suggested that IL-1β induced enhanced expression of FoxP3. Remarkably, we found that oral malignant transformation induced aberrant expression of TGF-β, a critical mediator secreted by regulator T cells (Treg) and IFN-γ, a major effector molecule of T Effector cells. Therefore, we hypothesize that, in oral precancerous microenvironment, IL-1β disrupt the immune homeostasis via inducing immune imbalance between Foxp+ Treg and IFN-γ+ T Effector cells, which will therefore induces the epithelia malignant transformation. To address this hypothesis, we will continuously use our expertise of 4NQO mouse model to elucidate the exact mechanisms in which IL-1β induces epithelia malignant transformation via mediating an aberrant immune balance between FoxP3+Treg / IFN-γ+T Effector cells. We will also investigate the clinical correlation between severity of precancerous lesion and expression of IL-1β/FoxP3 /IFN-γ. These findings will collectively shed new lights on roles of IL-1β-mediated inflammatory response in immune microenvironment during oral carcinogenesis and provide a potential new strategy for prevention and treatment of precancerous lesion.