PA28γ通过CCL-2/IL-6调节TAM重塑肿瘤微环境调控口腔鳞癌转移的机制与意义

Tumor-associated macrophages (TAM) based tumor immunotherapy strategies have been drawn greater attention in recently years. CCL-2 could recruit and polarize TAM promotes tumor growth and metastasis. How to block the expression of CCL-2 and IL-6 at same time is the leading edge emergency problem which could improve the efficiency of targeted TAM anti-tumor metastasis (Nature 2014). Our preliminary results suggested PA28γ overexpression is associated with adverse prognosis in patients with oral squamous cell carcinoma (OSCC). The aberrant expression of PA28γ contributed to the metastasis and progression of OSCC and induced the expression of CCL-2 and IL-6. We hypothesize that disturb PA28γ could interfered TAM and tumor microenvironment remodeling though CCL-2/IL-6 signaling to block metastasis in OSCC. For this purpose, cells co-culture models, clinical cohorts, animal models and other molecular research techniques will be used to study this project in the following areas: the role of PA28γ in the process of tumor cells and TAMs mutual induction and enlightenment, and in vascular remodeling with in tumor microenvironment; the mechanism and therapeutic effect of targeting PA28γ or it key regulatory factor to block CCL-2 and IL-6 for OSCC therapeutic. The implementation of this innovative project will not only help us understanding the basic biological processes of OSCC tumorigenicity and metastasis, but also provide some new ideas and lay the foundation for development of new tumor immunotherapy strategies which target PA28γ based “double” regulator of TAM.

基于肿瘤相关巨噬细胞（TAM）的免疫治疗近年备受关注，CCL-2可募集极化TAM促进肿瘤转移。如何在抑制CCL-2的同时阻遏IL-6信号，增强以TAM为靶标的抗肿瘤转移疗效，是急待解决的前沿问题（Nature 2014）。申请人前期发现：PA28γ是口腔鳞癌侵袭迁移预警新分子，可诱导肿瘤同时高表达CCL-2和IL-6。我们假定干预PA28γ将达到CCL2/IL-6双标同时阻断，调控TAM，重塑微环境，提高抑制肿瘤转移的效率。为此，本项目拟采用细胞，动物和临床队列等模型体系及各级分子调控手段，观察PA28γ在肿瘤细胞和TAM的相互诱导分化及瘤内血管生成中的作用，探讨干预PA28γ实现CCL-2/IL-6双标阻断重塑肿瘤微环境进而抑制肿瘤转移的分子调控机制和疗效。本项目的实施不仅将揭示口腔鳞癌的转移机制，更可为研发以PA28γ为靶标，实现针对TAM的“双重”调节的免疫治疗新策略奠定基础。

PA28γ促进肿瘤的发展和进展，并被认为在肿瘤血管生成中起作用，但具体机制仍不清楚。在本项目中，首先采用体外共培养细胞模型发现PA28γ促进OSCC细胞募集内皮细胞并诱导体外血管生成；采用动物模型发现PA28γ表达促进体内肿瘤诱导的血管生成；其次机制分析发现PA28γ以NF-κB/CCL2/CCR2 信号轴依赖的方式促进血管生成；继之，从蛋白水平探索了PA28γ的翻译后修饰方式，发现其磷酸化和糖基化位点；最后采用临床队列发现OSCC组织中PA28γ和CCL2及CCR2蛋白表达水平呈正相关关系。总体而言，我们的研究表明PA28γ通过调节IL-6和CCL2促进肿瘤血管生成。PA28γ可能作为IL-6和CCL2的双重调节剂成为治疗PA28γ阳OSCC的新型治疗靶标。除此以外，还发现PA28γ具有转录因子/转录辅因子的潜能，并发现U2AF1是PA28γ的共表达因子。该项目的执行及相关数据加深了我们对OSCC肿瘤微环境中血管生成机制的了解，可为寻找OSCC靶向血管生成治疗新靶点，发展新的OSCC治疗策略和方法，提供新的思路。