结直肠癌微环境中巨噬细胞IRE1α/XBP1信号通路的调控机制及作用研究

Immune microenvironment plays important roles in the multistep process of colorectal cancer from carcinogenesis to treatment. Currently, to improve traditional immunotherapy for colorectal cancer patients in clinic is getting into a bottleneck period. So, to find out new targets with some new strategies is urgent for us. Macrophages are one of the most abundant immune groups in intestine and contribute to tumor development and treatment. Macrophages in tumor microenvironment could be ”educated” to be tumor-promoting. Our previous result suggested that IRE1α/XBP1 pathway in macrophages could be regulated by microenvironment, and IRE1α/XBP1 pathway contributed to tumor-promoting function of macrophage. In this study, we will focus on the IRE1α/XBP1 pathway of macrophages in intestinal microenvironment. We will investigate the role of IRE1α/XBP1 pathway on development of colorectal cancer and clarify the regulatory mechanisms of IRE1α/XBP1 signal pathway in tumor microenvironment. By targeting XBP1, we will switch the function of macrophage from tumor-promoting to tumor-suppressing, and explore its application value in colorectal cancer. Our result will elucidate the regulatory mechanism of the endoplasmic reticulum stress response in macrophages and the potential of the IRE1α/XBP1 signaling pathway as a therapeutic target for colorectal cancer.

免疫微环境与结直肠癌发生发展及治疗效果密切相关。目前针对结直肠癌的免疫治疗研究遇到瓶颈，寻找新的靶点具有重要意义。肠道微环境中巨噬细胞含量丰富，在肿瘤微环境中经驯化后，发挥促瘤功能。本项目预实验结果提示结直肠肿瘤微环境的改变诱发巨噬细胞的内质网应激反应，激活IRE1α/XBP1信号通路，是巨噬细胞发挥促瘤功能的重要原因。因此，本项目选择巨噬细胞为研究对象，在细胞水平，动物模型和人体标本研究巨噬细胞IRE1α/XBP1信号通路与结直肠癌发生、发展、转移的相关性；研究结直肠癌微环境中巨噬细胞IRE1α/XBP1信号通路的调控网络；并通过靶向巨噬细胞IRE1α/XBP1信号通路来改变巨噬细胞的功能，使得其从促瘤向抑瘤方向转化。本项目将阐明结直肠癌微环境中巨噬细胞内质网应激反应的调控机制，探讨巨噬细胞IRE1α/XBP1信号通路作为结直肠癌免疫干预靶点的潜在可能性。

巨噬细胞是结直肠癌中最丰富的免疫细胞之一。重新驯化肿瘤相关巨噬细胞使其从促肿瘤活性转变为抗肿瘤活性是一种有吸引力的治疗策略，值得进一步研究。然而，关于在TAMs中激活的关键途径知之甚少。该研究对结直肠癌浸润的肿瘤相关巨噬细胞进行分选并进行RNA-seq分析。结果发现差异表达的基因在未折叠蛋白反应/内质网应激反应通路中富集，并且存在XBP1基因的剪接/激活。在人结直肠癌组织及动物模型中均发现XBP1s的过表达现象。小鼠模型中TAMs中XBP1的激活促进了结直肠癌细胞的生长和转移。敲除XBP1可以改变TAMs的细胞因子表达特征，促肿瘤细胞因子包括 IL-6、VEGFA 和 IL-4等受到抑制。同时，XBP1敲除可直接抑制SIRPα和THBS1的表达，从而阻断“不要吃我”的细胞自我识别信号并增强吞噬作用。利用AAV2-sgXBP1治疗性敲除XBP1基因显著抑制小鼠模型中肠癌的发生。总之，TAMs中的XBP1通路激活通过提高促肿瘤细胞因子的表达以及抑制巨噬细胞吞噬作用来驱动结直肠癌进展。该研究结果表明TAMs中的XBP1具有作为结肠癌治疗新靶点的潜力。