Wnt信号通路靶基因ASCL2调节CMS2型结直肠癌荒漠型肿瘤免疫微环境的分子机制及其临床意义

目前，免疫检查点抑制剂(ICI)已成功用于治疗MSI-H型转移性结直肠癌(CRC)患者。然而，MSI-H型患者仅占10%左右，其他类型CRC因表现为荒漠型免疫微环境，对ICI治疗不敏感；能否联合其他治疗使该部分患者逆转为免疫炎症型肿瘤，已成为目前研究的热点问题。我们前期发现，Wnt通路靶基因ASCL2可能参与CMS2型CRC肿瘤细胞干性维持及荒漠型微环境调控。鉴于此，我们提出“在CMS2型CRC中，ASCL2表达上调转录激活抑炎因子IL-10的表达，降低NF-κB等炎症通路活性，调节荒漠型免疫微环境形成，引起ICI治疗抵抗”这一科学假设。本课题拟利用肠道条件性基因敲除、人源肿瘤异种移植(PDX)等小鼠模型，明确ASCL2调控CMS2型CRC荒漠型免疫微环境的分子机制，并探讨Wnt通路/IL-10抑制剂联合ICI治疗荒漠型CRC的可行性；以期为晚期CMS2型CRC患者提供一种新的治疗策略。

Currently, immunocheckpoint inhibitors (ICI) have been successfully used in the treatment of metastatic colorectal cancer (mCRC) patients with MSI-H. However, MSI-H patients only accounted for about 10%, and other types of CRC were not sensitive to ICI treatment due to their desert immune microenvironment. Whether it can be combined with other treatments to turn into immune inflammatory tumor in these patients will greatly expand the application scope of ICI. We previously found that ASCL2, a target gene of the Wnt pathway, was significantly up-regulated in CRC and negatively correlated with intratumoral immune cell infiltration. In view of this, we propose the scientific hypothesis that "In CMS2 CRC, ASCL2 expression upregulation transcriptionally activates the expression of anti-inflammatory factor IL-10, reduces the activity of inflammatory pathways such as NF-κB, regulates the formation of desert immune microenvironment, and results in ICI therapeutic resistance". This project intends to clarify the molecular mechanism of ASCL2 regulation on desert immune microenvironment in CMS2 CRC using the intestinal conditional gene knockout mice and other models, and to investigate the feasibility of Wnt pathway/IL-10 inhibitor combined with ICI in the treatment of CRC with desert immune microenvironment by using human tumor xenotransplantation (PDX) and other models. The successful completion of this project is expected to provide a new treatment strategy for advanced CMS2 CRC patients.