结肠癌易复发和转移,免疫疗法是其重要的治疗方式。研究表明IL-1β具有抗结肠癌作用,但其作用具有浓度依赖性。TLR4及NLRP3通路调控IL-1β的生成和分泌，固有免疫细胞及结肠癌细胞有TLR4及NLRP3通路关键受体的表达。如何促进上述细胞中IL-1β的生成是抗结肠癌复发转移的关键。脂多糖(LPS)和溶细胞素蛋白(ClyA)分别是TLR4及NLRP3信号通路活化的重要配体。本课题组前期已通过基因重组技术合成了工程化沙门氏菌(S.t-ΔpGlux/ pT-ClyA),但其是否能通过促进IL-1β的高通量生成而抑制结肠癌复发转移尚不明确。为此我们拟通过MRI技术对重组工程菌治疗结肠癌的疗效进行动态评估,通过细胞学、分子生物学等技术来探讨工程菌治疗结肠癌时IL-1β的来源细胞及IL-1β表达变化对肿瘤细胞、免疫细胞的影响,并分析其调控机制。本研究将为结肠癌的治疗提供新的思路。

Colon cancer has a high risk of recurrence and metastasis. Immunotherapy is an important treatment modality for it. Studies have shown that IL-1β has anti-tumor effect, but it plays the roles in a concentration dependent manner. TLR4 and NLRP3 signal pathways regulate the production and secretion of IL-1β. The key receptors of TLR4 and NLRP3 signal pathways were expressed in innate immune cells and colon cancer cells. How to upregulate the production of IL-1β in these cells is the key point to inhibit the recurrence and metastasis of colon cancer. Lipopolysaccharide (LPS) and cytolysin (ClyA) are important ligands of TLR4 and NLRP3 signal pathway, respectively. We have constructed a engineered salmonella (S.t-ΔpGlux/pT-ClyA) for the combination of LPS and ClyA using genetic recombination technology. Whether the engineered salmonella plays a role in the treatment of colon cancer by promoting the generation of IL-1β remains unclear. MRI will be used to assess the treatment efficacy of engineered salmonella. Cellular and molecular biology techniques will be used to investigate the cells source of IL-1β and explore the function of IL-1β in tumor cells and immune cells. And the regulatory mechanism of the IL-1β will be analyzed. This study will provide new ideas of the colon cancer treatment.