双链DNA介导喜树碱类药物激活免疫应答机制研究

Cytotoxic drugs have a long history and play a dominant role in the clinical treatment of advanced tumors. In recent years, the concept of tumor therapy has been constantly changing, which opens up a new opportunity for the clinical use of cytotoxic drugs. In addition to tumor cells themselves, cytotoxic drugs can extensively act on a variety of immune cells in the tumor microenvironment, affecting the immune response, but the related molecular mechanisms still need to be studied. To elucidate the effect and molecular mechanism of cytotoxic drugs on the immune system will help us better understand the anti-tumor mechanism of cytotoxic drugs, and hopefully find the opportunity of combined therapy with tumor immunotherapy. Previous studies of this project have found that camptothecin drugs can induce intestinal epithelial cells and tumor cells to release double-strand DNA, activate the AIM2 inflammatory pathway of innate immune cells, and cause intestinal damage. As an immunogenic substance, double-stranded DNA may activate multiple immune response pathways in immune cells. On the basis of the previous work, this project aims to explore the molecular mechanism of camptothecin drugs in activating the immune response and the effect combined with immunotherapy by focusing on the intrinsic immune cells and focusing on the double-stranded DNA released by tumor cells induced by drugs, in order to provide important information for the clinical exploration of combined immunotherapy with cytotoxic drugs.

传统细胞毒类药物历史悠久，在晚期肿瘤的临床治疗中占有主导地位。近年来，肿瘤治疗理念不断变革，为细胞毒药物的临床使用开辟了新的契机。除了肿瘤细胞自身，细胞毒药物可以广泛作用于肿瘤微环境中的多种免疫细胞，影响免疫应答的多个环节，但是相关的分子机制还有待系统深入地研究。阐明细胞毒药物对免疫系统的作用和分子机制，将更好地认识细胞毒药物的抗肿瘤作用的机制，并有望发现与肿瘤免疫治疗联用的治疗契机。本项目前期研究发现，喜树碱类细胞毒药物可以通过诱导肠道上皮细胞和肿瘤细胞释放双链DNA，激活固有免疫细胞的AIM2炎症小体通路，造成肠道损伤。双链DNA作为免疫原性物质，可能激活免疫细胞中的多条免疫应答通路。本项目拟在前期工作的基础上，以药物引起肿瘤细胞释放的双链DNA为核心，聚焦固有免疫细胞，探索喜树碱类药物激活免疫应答的分子机制及与免疫治疗联用的效果，旨在为细胞毒药物联合免疫治疗的临床探索提供重要信息。

肠道微环境对免疫治疗的疗效具有重要作用，DNA损伤药物对肠道菌群的影响正得到越来越多的认识。但尚不清楚化疗引起的基因组应激是如何转化为肠道微环境的改变的。在本研究中，我们发现DNA损伤化疗药物特异性地导致肠道免疫微环境激活。从机制上讲，回肠隐窝中的瞬时增殖细胞（Transit amplifying cells， TACs）的快速增殖状态对化疗引起的基因组应激更为敏感，进而导致胞质双链DNA（dsDNA）的积累，随后激活dsDNA受体。dsDNA受体激活进一步增强会场粘膜固有层的Th1细胞免疫，从而激活肠道固有层免疫微环境，重塑远端肿瘤免疫微环境。.综上，本研究揭示了dsDNA在介导化疗引起的肠道免疫微环境重构中的作用，为化疗-肠道相互作用提供了机制见解，并为癌症免疫治疗的新治疗策略提供了信息。