Wnt信号通路抑制剂调控肿瘤免疫微环境的机制研究

Colorectal cancer is the third most prevalent cancer in China. The Wnt/β-catenin (β-cat) pathway plays a critical role in cancer initiation and progression and β-cat is an important target for cancer therapy. Recent studies also reported an emerging role of Wnt/β-cat in evading immune surveillance and inhibition of Wnt signaling activity could potential improve immuno-therapy outcome. In our previous study, we developed a hydro-carbon stapled peptide inhibitor targeting oncogenic Wnt activity by disrupting the interaction of β-cat with its co-activators B-cell lymphoma 9 (BCL9) and its homologue B-cell lymphoma 9-like (B9L). We further optimized the parental peptide and generated a new series of peptides. These newly generated stapled peptide inhibitors show strong anti-tumor efficacy and tolerability. In this study, we will take advantage of cellular models, animal models and patient samples. We will investigate the mechanism of inhibition of β-cat transcription activity in colorectal cancer development, to understand the molecular mechanism of targeting Wnt signaling pathway to modulate tumor immuno microenvironment and to explore synergy between Wnt inhibitor and checkpoint inhibitor in vivo. Outcome of this research will not only provide a new approach for cancer immuno-therapy but also scientific basis for clinical study. . The applicant of this grant proposal has accumulated extensive experience in this field and two of his selected first author publications are about tumor microenvironment research (Nature Medicine, 2015) and oncogenic Wnt inhibitor development (Science Translational Medicine, 2012). Based on our preliminary data, we found inhibition of β-catenin transcriptional activity promotes immune cell tumor infiltration and changes related chemokine/cytokine expression. In this grant proposal, we will further investigate the molecular mechanism of Wnt signaling pathway in regulating CD8+T cells and Treg cells tumor infiltration and uncover the chemokine and cytokine which could induce CD8+T cells and Treg cells migration. The purpose of this study is to provide the science basis for immunotherapy development targeting to β-cat/BCL9 as well as for future clinical trial design of combination therapy between Wnt inhibitor and checkpoint blocker antibodies.

结直肠癌是我国发病率第三位的癌症。Wnt/β-catenin信号通路异常活化是结直肠癌发生发展的重要原因，也是临床治疗的重要靶点。同时Wnt信号通路也参与调节肿瘤免疫微环境，可能影响免疫治疗的效果。申请人前期工作发现靶向β-catenin/BCL9的Wnt信号通路抑制剂（Science Translational Medicine,2012），并立足于之前在肿瘤微环境的经验（Nature Medicine,2015），已发现抑制β-catenin转录对于CD8+T细胞和Treg细胞肿瘤浸润有重要影响，同时调节趋化因子和细胞因子的表达。本项目将利用细胞、小鼠模型和临床标本，确认抑制Wnt信号通路对结直肠癌发生发展的重要性和机制；研究Wnt通路调控肿瘤免疫微环境的分子机制及干预方法；探讨Wnt信号抑制剂增强免疫治疗的效果。相关研究成果能够为肿瘤免疫治疗提供新的手段，为临床免疫联用提供理论基础。

结直肠癌是我国发病率第三位的癌症。Wnt/β-catenin信号通路异常活化是结直肠癌发生发展的重要原因，也是临床治疗的重要靶点。本项目聚焦Wnt信号通路参与调节肿瘤免疫微环境和免疫治疗开展了系统的研究。项目主要成果：1.阐明BCL9/β-catenin介导的肿瘤免疫耐药机理。2.开发靶向BCL9/β-catenin的新药分子。3.开发突破肿瘤免疫耐药的新疗法。这些工作验证了BCL9作为肿瘤免疫治疗新靶点，发现一系列新的肿瘤免疫治疗方法并开展转化，代表性工作发表在Cancer Discov.，Sci. Adv.，Signal Transduct Target Ther.等杂志，并完成成果转化。本项目发现的BCL9介导免疫耐药机制，验证了高应用性的免疫治疗新靶点，为新药开发和未来的临床试验提供理论基础。