以细菌外膜为基础的双级递氧纳米体系的构建及其在增强放疗引起的抗肿瘤免疫反应中的作用研究

In recent years, it has been found that, in addition to direct cell damage, radiotherapy can also promote the systemic anti-tumor immune response and inhibit or even completely eliminate the non-irradiated distal tumor growth. This phenomenon has aroused great interest and was commented by Nature magazine as a hope to completely change the status of anti-cancer treatment. However, according to statistics, the clinical incidence of anti-tumor immune response caused by radiation therapy is very low. In our previous study, we found for the first time that bacterial outer membrane vesicles increased the anti-tumor immune response of radiotherapy. For this reason, in this project, we will build a two-order O2 delivery system based on the bacterial outer membrane. We expect to improve the tumor hypoxia microenvironment by continuous supply of O2, and then increase the activation of DC cells under the immunostimulation of bacterial outer membrane, promote DC uptake and presentation of tumor antigens after radiotherapy, and finally increase anti-tumor immune response. We hope that through the study of this project, we can provide new ideas and solutions for anti-tumor treatment.

近年来发现，放疗除了能产生直接的细胞损伤之外，还可以促进全身的抗肿瘤免疫反应，并使未受放射照射的远端肿瘤生长受到抑制甚至完全消失。这一现象激起了人们极大兴趣，并被Nature杂志评论为有望彻底改变抗肿瘤治疗现状。然而，数据统计显示，临床上放疗引起的抗肿瘤免疫反应依然非常罕见。在我们前期的研究中，我们首次发现细菌外膜囊泡能增加放疗的抗肿瘤免疫反应。为此，在本项目中，我们以细菌外膜为基础，构建双级递氧纳米体系，期望通过持续供给氧气，改善肿瘤乏氧微环境，再利用细菌外膜对免疫细胞的招募和刺激，最终增加放疗的抗肿瘤免疫反应。期望通过本项目研究，能够为抗肿瘤治疗提供新的思路和解决方案。

目前放疗引起的全身抗肿瘤免疫效应依然非常罕见，实体肿瘤内部的乏氧微环境可能是导致放疗抗肿瘤免疫发生率低的原因之一。为此，我们期望使用载体向肿瘤递送氧气，改善抗肿瘤免疫反应。在本项目中，我们成功构建了基于细菌的递送平台，一方面通过工程菌的佐剂作用招募更多的免疫细胞，另一方面通过局部供氧，为免疫细胞提供一个有利的免疫反应微环境。通过本项目的研究，我们发现原位疫苗对肿瘤免疫反应激活的关键在于免疫细胞的数量和状态，佐剂效应可增加免疫细胞数量而氧气则为免疫细胞提供了适宜的微环境。通过本项目的研究，为放疗原位疫苗的设计提供了新的研究思路和科学数据支撑。