Wnt/β-catenin通路在Niclosamide增强非小细胞肺癌免疫治疗疗效中的作用机制研究

单药免疫治疗仅适用于20%的非小细胞肺癌人群，免疫联合治疗则可通过协同机制激活免疫应答扩大应用人群。我们前期研究证实抗绦虫药Niclosamide(NM)与PD-L1单抗联用可增加肺癌免疫治疗疗效；进一步机制探索发现NM可抑制肿瘤细胞内Wnt/β-catenin信号通路，上调趋化因子CCL4表达。基于CCL4可招募树突状细胞（DCs）并促进其Th1型趋化因子分泌，进而招募CD8+ T细胞进入肿瘤组织的免疫学知识，我们提出“NM通过抑制肿瘤细胞内Wnt/β-catenin通路上调CCL4表达，招募DCs并分泌趋化因子，增强CD8+ T细胞浸润，从而增加PD-L1单抗疗效”的科学假说。本项目拟通过基因编辑及多重免疫共染等方法，阐明NM抑制Wnt/β-catenin通路进而上调CCL4的具体机制；结合动物及临床验证，最终获得NM联用提高肺癌免疫治疗疗效的可靠证据，为开展后续临床研究提供科学依据。

Monotherapy of immune checkpoint inhibitor (ICI) is considered only applicable to about 20% patients with non-small cell lung cancer (NSCLC), however, the combinational immunotherapy strategy can rewire the tumor microenvironment and act a synergistic anti-tumor effect, leading to broader target beneficiaries of NSCLC. We have previously reported the efficacy of PD-L1 antibody (Ab) to NSCLC can be promoted by niclosamide in vitro and in vivo. Further exploration shows that niclosamide can inhibit Wnt/β-catenin signaling pathway and further upregulate CCL4 expression. Based on the immune knowledge that dendritic cells (DCs) can be recruited by CCL4 and significantly secrete Th1-type chemokines, contributing to CD8+ T cells infiltrating into tumor. We propose that niclosamide can enhance the immunotherapeutic efficacy of PD-L1 Ab by inhibiting Wnt/β-catenin signaling pathway, upregulating CCL4, recruiting DCs as well as promoting secretion of Th1-type chemokines, and finally increasing the tumor infiltrated CD8+ T cells. Our project aims to elucidate the underlying mechanism of how niclosamide suppress Wnt/β-catenin pathway and upregulate the expression of CCL4 by such advanced technics including gene editing, multiplexed immunohistochemistry and so on. Combined with animal model and clinical validation, eventually we will obtain the reliable evidence of improved immunotherapeutic efficacy by synergistically combining niclosamide with ICI for NSCLC, and provide the scientific basis for conducting the future clinical research.