BCL9/9L调节T细胞的肿瘤浸润改善PD-1治疗耐药的研究

结肠癌是我国发病率第三位的癌症，免疫治疗响应率低。Wnt信号通路异常活化是结肠癌发生发展的重要原因并调节肿瘤免疫微环境，但是调控机制不明。BCL9/9L是β-catenin重要的转录激活因子，申请人前期工作发现靶向BCL9/β-catenin的抑制剂（Sci Transl Med.，2012）和发现该抑制剂调控T细胞的肿瘤浸润（Sci Adv.，2019），立足于肿瘤微环境的经验（Nat Med.，2015），已发现敲低BCL9/9L对于T细胞肿瘤浸润和PD-1治疗响应有重要影响。本项目将利用Bcl9/9l转基因小鼠模型，确认BCL9/9L在免疫细胞和肿瘤细胞中通过介导Wnt信号影响肿瘤微环境，阐明BCL9/9L敲除对于促进PD-1的响应机制，为BCL9/9L作为结直肠癌免疫治疗的新靶标提供理论依据。

Colorectal cancer is the third most common cancer in China. The deregulation of Wnt/β-catenin signaling pathway plays an important role in the development of colorectal cancer and modulates tumor immuno micro environment. BCL9/9L is a critical transcription co-activator of β-catenin. Our previous work identified stapled peptide inhibitor targeting BCL9/β-catenin to inhibit oncogenic Wnt signaling (Sci Transl Med., 2012), and also found disruption binding of BCL9 and β-catenin modulates CD8+ T cells and Treg tumor infiltration (Sci Adv., 2019). We also accumulated extensive experience in the field of tumor microenvironment (Nat Med., 2015). In our recent work, we found that depletion of BCL9/9L promotes CD8+ T and reduces Treg cell tumor infiltration. In this proposal we will take advantage of Bcl9/9l knock out transgenic mouse models to investigate the role of BCL9/9L role in regulation of cytokines, chemokines and their receptors via mediating Wnt/β-catenin signals in the tumor immune microenvironment. Our aim is to confirm BCL9/9L as a novel target for colorectal cancer immunotherapy as well as to elucidate the mechanism of BCL9/9L knockout to promote the response of immune checkpoint inhibitors.