TLR2激动剂促T细胞抗脑胶质瘤免疫应答的机制研究

Toll-like receptors (TLRs) are a type of pattern recognition receptors, which induce immune response by recognizing pathogen-associated molecular patterns. Under physiological condition, TLRs mainly express on innate immune cells. Recently, it was found that TLRs play a direct role in adaptive immune cells, including T cells, and mediate adaptive immune response. Our previous study suggested that TLR2 agonist reciprocally mediates T cell subsets so as to enhance anti-tumor immunity in lung cancer. Moreover, TLR2 agonist maintains T cell survival in glioma-bearing host, but the underlying mechanisms need be further investigated. In this study, glioma-bearing mice are as a model, T cells are as objects, and immunology, cellular biology and molecular biology are as methods. Firstly, it will be verified that TLR2 agonist induces T cell-mediated anti-glioma immunity by maintaining T cell survival in vivo. Then, the role of TLR2 signal in T cell survival is investigated in vitro. After that, the relationship of TLR2 signaling and T cell activation signaling is evaluated. Furthermore, knock-out mice are used to confirm the above results in vivo. Our data hopefully will enrich TLRs theory and might expand the application of TLRs in anti-tumor immunotherapy, which is of great significance.

Toll样受体属模式识别受体，通过识别病原相关分子模式诱导免疫应答。TLRs主要表达于固有免疫细胞，近期的研究亦发现TLRs直接作用于T细胞等适应性免疫细胞发挥效应。我们前期研究发现，在肺肿瘤模型中，TLR2激动剂可差异性作用于不同T细胞亚群，增强抗肿瘤免疫应答。此外，在脑胶质瘤模型中，我们发现TLR2激动剂维持T细胞长期存活，促其发挥抗肿瘤免疫效应，其机制待阐明。基于此，本研究拟以脑胶质瘤原位荷瘤小鼠为模型，以T细胞为研究对象，利用免疫学、细胞生物学和分子生物学等方法，首先明确TLR2激动剂维持T细胞存活促其抗肿瘤免疫应答。接着，研究TLR2信号在T细胞存活中发挥的作用。而后，探寻TLR2信号与T细胞活化信号之间的相互关系及其分子机制。进一步，研究并验证TLR2信号在荷瘤机体内维持T细胞长期存活的可能机制。该研究希望丰富TLRs的相关机制，拓展其在肿瘤免疫生物治疗中的应用，具有重要意义。

Toll样受体既表达于固有免疫细胞，又表达于T细胞等适应性免疫细胞，并通过多种机制发挥效应。我们前期研究发现，在荷瘤小鼠模型中，TLR2激动剂BLP维持T细胞长期存活，促其发挥抗肿瘤免疫效应，相关机制待阐明。因此，本研究以荷瘤小鼠为模型，以TLR2信号为切入点，以T细胞为研究对象，利用免疫学、细胞生物学和分子生物学等方法，研究了TLR2激动剂维持T细胞活化、增殖和生存的可能机制。结果表明，TLR2激动剂BLP通过提供共刺激信号的直接方式维持T细胞生存，这一效应依赖于P38、NF-kB通路。同时还发现，TLR2激动剂BLP通过促髓系来源的抑制性细胞向M1型巨噬细胞分化成熟，上调共刺激分子表达等，既逆转其对T细胞的免疫抑制功能，又进一步向T细胞提供共刺激信号，以间接方式维持T细胞活化、增殖和生存，这一效应依赖JNK通路。因此，TLR2激动剂BLP可通过直接和间接两种方式双向促进T细胞功能，进而诱导增强的抗肿瘤免疫应答。该研究成果将有助于丰富Toll样受体免疫识别和调控等相关机制，更为TLR2激动剂临床肿瘤治疗提供理论和实验基础，具有十分重要的现实意义。