肿瘤的免疫逃逸是复发转移的重要机制，其分子基础尚不完全明了。申请者前期在端粒调控相关研究中发现：含端粒序列RNA(TERRA)在结肠癌细胞中异常增高，标记示踪发现癌细胞来源的TERRA在巨噬细胞内异常聚集，预实验提示TERRA与巨噬细胞内免疫抑制分子SIRPα的启动子区域存在间接作用，是转录因子ELK激活SIRPα表达的重要前提。而SIRPα是已知抑制巨噬细胞吞噬的受体。我们推测：肠癌细胞来源的TERRA可通过外泌体进入肿瘤相关巨噬细胞，与ELK1、HIF1α相互作用并转录激活SIRPα表达，后者能识别肿瘤细胞膜上的CD47并抑制巨噬细胞对其吞噬。本研究拟利用分子克隆、细胞和动物模型，在巨噬细胞中解析TERRA与HIF1α、ELK-1的互作用及其对SIRPα的激活效应；并在动物模型中验证上述通路对肠癌天然免疫的影响。本研究将为结肠癌改变微环境天然免疫细胞功能提供分子机制和潜在的治疗靶点。

Immune escape of tumor cell is the main cause of cancer recurrence and metastasis, with its molecular mechanism still unknown. In our previous studies on telomere regulation we revealed that telomere-containing RNA (TERRA) was abnormally increased in colon cancer cells. Nucleic acid tracing revealed that TERRA derived from cancer cells was abnormally aggregated in macrophages. Preliminary experiments suggested that TERRA interacts with SIRPα promoter regions in macrophages, and this interaction is an important prerequisite for the activation of SIRPα by transcription factor ELK. SIRPα is a known inhibitory receptor for macrophage phagocytosis. We speculate that TERRA derived from colon cancer cells can enter tumor-related macrophages through exosomes, interact with ELK1 and HIF1 alpha, and transcriptly activate SIRP α, which induces tumors immune escape by inhibiting macrophage phagocytosis through SIRP α-CD47 inhibitory signal. We hereby proposes to use Cell and animal models to investigate the interaction mechanism between TERRA and HIF1α and ELK-1 in macrophages and their activative effects on SIRPα. We will verify the innate immune escape effects of this pathway in animal models. This study will provide molecular insights on how colon cancer cells change the innate immune profile of the tumor microenvironment.