TLR8介导卵巢癌Tregs免疫抑制功能逆转的分子机制研究

Immunosuppresion in ovarian cancer microenvironment is the great obstacle for its curative effect. Regulatory T cells played critical role in forming immunosuppressive microenvironment of ovarian cancer. We found that the activation of Toll-like receptor (TLR)-8 signaling could reverse the suppressive function from ovarian cancer-derived CD4+ Tregs and CD8+ Tregs. However, the molecular mechanism remains largely unknown. Our previous experiments indicated that the alternations of cellular glucose metabolism correlated with suppressive function reversal of ovarian cancer-specific Tregs regulated by TLR8 signaling, and mTOR signaling pathway was involved. We hypothesize that TLR8 could activate mTOR singaling pathway, and this progress results in activation of ovarian tumor-derived Tregs. Meanwhile, the cellular glucose metabolism in ovarian cancer-derived Tregs was altered, which gave rise to the reversal of Treg suppressive function. In this way, hindrance of immune tolerance was broken, and with enhanced anti-tumor immunity. In this project, we firstly study whether or not the reversal of suppressive function in Tregs via TLR8-mediated derived from metabolic alternation of Tregs. Next, we clarify the key role of mTOR signaling pathway in alternation of glucose metabolism and suppressive function reversal of Tregs mediated by TLR8 activation. Finally, we will manipulate the TLR8 signaling pathway to controll the glucose metabolism of Tregs, and to enhance anti-tumor immunity response in mice models with transgenic human TLR8 and NOD-SCID ovarian cancer mice models. This project will lay a theoretical foundation and will new strategies for ovarian cancer immunotherapy based on reversal of suppressive function in Tregs.

卵巢癌微环境中的免疫抑制是其疗效的重大障碍，Tregs是卵巢癌免疫抑制微环境形成的重要因素。我们发现TLR8配体能逆转卵巢癌CD4+Tregs及CD8+Tregs的抑制功能，但其分子机制不明确。预实验提示TLR8介导卵巢癌Tregs抑制功能的逆转与细胞糖代谢改变有关，并涉及mTOR信号途径。在此基础上我们提出假设：卵巢癌Tregs在TLR8介导下活化mTOR信号途径，从而影响Tregs糖代谢平衡，逆转其抑制功能，打破Tregs在肿瘤微环境中形成的免疫耐受壁垒，提高机体抗肿瘤免疫。本项目首先探究TLR8介导Tregs抑制功能的逆转是否源于Tregs糖代谢改变；其次阐明mTOR信号途径是TLR8介导的糖代谢改变及Tregs功能逆转的关键；最后在动物体内研究操纵TLR8信号控制Tregs的糖代谢可提高机体抗肿瘤免疫。本研究将为基于卵巢癌Tregs抑制功能逆转的免疫治疗奠定理论基础及提供新策略。

本项目前期研究发现TLR8配体能逆转卵巢癌来源的Tregs的抑制功能，TLR8介导的卵巢癌Tregs抑制功能的逆转涉及mTOR信号途径。因此，本项目提出卵巢癌微环境中Tregs在TLR8信号介导下活化mTOR信号途径，从而影响Tregs的糖代谢平衡，逆转其免疫抑制功能，打破Tregs在卵巢癌微环境中形成的免疫耐受壁垒，提高机体抗肿瘤免疫。为阐明上述设想，本项目首先探究TLR8介导的Tregs免疫抑制功能的逆转源于Tregs糖代谢的改变；其次阐明mTOR信号途径是TLR8介导的Tregs糖代谢调控及抑制功能逆转的关键；最后在动物体内研究操纵Tregs的糖代谢及TLR8信号可提高机体抗肿瘤免疫。.本项目的研究发现TLR8信号可以调控与卵巢癌细胞共培养的CD4+ T细胞糖酵解代谢与功能的改变；TLR8信号介导的卵巢癌细胞共培养微环境中Treg细胞的抑制功能逆转与糖代谢之间存在因果关系；TLR8 信号可通过下调 mTOR 信号来抑制CD4+ Tregs的糖代谢从而发挥对CD4+ Tregs 的免疫抑制功能逆转作用；在动物体内操纵Tregs的糖代谢及TLR8信号可提高机体抗肿瘤免疫。.研究结果初步阐明了TLR信号、T细胞能量代谢，mTOR信号通路，及Tregs免疫抑制功能之间的联系，提高了我们对TLR8信号途径调节Tregs糖代谢的分子机制的理解，及其与mTOR信号途径共同调控Tregs抑制功能逆转的分子机制；通过TLR8介导逆转Tregs的抑制功能在动物体内可提高机体抗肿瘤免疫；本研究为基于卵巢癌Tregs抑制功能逆转的免疫治疗奠定理论基础及提供新策略，也为TLR8配体可用于临床治疗干预奠定基础。