细胞外基质维度和硬度对树突状细胞运动能力和免疫学功能的影响及其分子机制的研究

The generations and developments of cancers are often accompanied by their significant inhibition on the immune functions of host. Tumors can escape from the surveillance of immune system in a variety of ways. DCs are the most powerful antigen presenting cells, which play a crucial role in the initiation of immune responses against cancer. The numbers of DCs in tumor tissues are negatively correlative with their infiltration degrees. As known now, the immune functions of DCs are markedly impaired by tumors-derived biochemical factors. The motility of DCs is one of the prerequisites for DCs’immune functions. However, in the tumor microenvironments, the effects of the special biomechanical microenvironment due to the changes in the stiffness and dimensions of tumor extracellular matrix remodeling that is different from normal tissue on the immune function of DCs are still elusive. Based our previous studies, therefore, the extracellular biomechanical environment with different dimensions and stiffness in vitro are constructed by fibrin or collagen hydrogel, whose effects on the biomechanical characteristics, motilities and immune functions of DCs as well as underlying molecular mechanisms will be investigated. Its most significant for further understanding immune escape mechanism of cancer, biological functions of DCs and improving the clinical efficiency of DCs-based immunotherapy against cancers.

肿瘤的发生发展往往伴随着其对宿主免疫功能的显著抑制，肿瘤可以通过多种方式逃脱免疫系统的监视。树突状细胞（dendritic cells, DCs）作为机体内最为强大的抗原提呈细胞，在抗肿瘤免疫应答的启动过程中发挥着关键作用。肿瘤组织内DCs数量与肿瘤浸润程度呈负相关。现已知道，肿瘤来源的生物化学因素严重损伤了DCs的免疫功能。DCs的迁移能力是其发挥免疫学功能的必要条件之一。然而，在肿瘤微环境内，由于肿瘤细胞外基质重塑引起其维度和硬度的改变而形成新的、异于正常组织的力学环境对DCs的迁移能力和免疫功能的影响目前还不清楚。因此，本课题利用纤维蛋白或胶原等在体外构建不同硬度和维度的细胞外生物力学环境，研究其对DCs生物力学特性、迁移能力和免疫学功能的影响及其潜在的分子机制，这对深入理解肿瘤的免疫逃逸机制、DCs的生物学功能和改善基于DCs的抗肿瘤免疫治疗的临床效率来说具有重要意义。

肿瘤的发生发展往往伴随着其对宿主免疫功能的显著抑制，肿瘤可以通过多种方式逃脱免疫系统的监视。树突状细胞（dendritic cells, DCs）作为机体内最为强大的抗原提呈细胞，在抗肿瘤免疫应答的启动过程中发挥着关键作用。肿瘤组织内DCs数量与肿瘤浸润程度呈负相关。现已知道，肿瘤来源的生物化学因素严重损伤了DCs的免疫功能。DCs的迁移能力是其发挥免疫学功能的必要条件之一。然而，在肿瘤微环境内，由于肿瘤细胞外基质重塑引起其维度和硬度的改变而形成新的、异于正常组织的力学环境对DCs的迁移能力和免疫功能的影响目前还不清楚。因此，本课题利用纤维蛋白或胶原等在体外构建不同硬度和维度的细胞外生物力学环境，研究其对DCs生物力学特性、迁移能力和免疫学功能的影响及其潜在的分子机制。研究结果表明，细胞外基质的硬度和维度能显著改变DCs的细胞形态，影响细胞骨架结合蛋白的表达及细胞骨架的动态重构，损伤DCs的生物力学特性（渗透脆性、杨氏模量）、运动能力、吞噬能力和刺激T细胞活化的能力。研究结果提示DCs的功能特性与其所处力学微环境密切相关，DCs能够感受细胞外微环境的力学刺激，并做出相应响应，而肿瘤微环境内异常的力学因素（维度和硬度等）可能是肿瘤损伤DCs的免疫功能，进而发生免疫逃逸的重要机制，这对进一步理解DCs的生物学行为和肿瘤的免疫逃逸机制具有重要意义，为改善基于DCs的肿瘤疫苗的临床治疗效率提供了理论依据。