口腔癌前病损转化微环境中IL-1β介导Treg/ T Effector免疫失衡的功能及机制

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.

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。

根据本项目申请书的研究目的和研究方案，本课题组研究计划主要集中在探讨IL-1β等关键节点在口腔黏膜免疫微环境中的免疫调控机制，及其对于口腔上皮恶性转化的推动作用，开展细胞-动物模型-临床样本三个层次的实验：① 细胞实验：通过体外实验发现IL-1β通过调控上皮细胞微环境氧化还原稳态，促进上皮恶性转化的持续进行；②动物实验：主要通过将单细胞测序技术应用于前期构建的4NQO诱导大鼠口腔癌模型，初步探讨口腔上皮恶性转化过程中免疫细胞，尤其是髓系抑制细胞（Myeloid-derived suppressor cells，MDSCs ）的时空改变；③临床样本实验：收集患者临床数据，结合数据库分析，探讨代谢异常与口腔癌预后关系。本项目资助期间共发表SCI文章5篇，累积影响因子19分，相关研究成果获得教育部2019年高等学校科学研究科学技术进步奖（第四完成人），题目：炎-癌转化调控网络在口腔黏膜潜在恶性疾患诊疗中的转化研究。本项目研究成果以期催生口腔癌前损害干预新策略，同时为其他炎症相关恶性肿瘤免疫调控网络和分子机制的研究、早期诊断与干预靶点的探讨等提供实验新依据和研究新思路。