Notch信号通过乳酸转运体调控TAMs极化和功能及在肿瘤进展中的作用机制研究

巨噬细胞是固有免疫的重要组成部分。在不同炎性刺激下，表现出不同的极化和功能状态。在肿瘤发生发展的各个阶段，肿瘤相关巨噬细胞（TAM）的极化和功能转变都会参与其中。肿瘤微环境中多种因素可以影响TAM的极化和功能重塑，其中肿瘤细胞的Warburg效应会导致微环境中乳酸堆积，高浓度乳酸可促进TAM向促肿瘤的的M2型极化转变，促进血管新生和肿瘤进展。申请人前期研究发现，Notch信号可教育TAM形成抗肿瘤的M1样极化，改善微环境，抑制肿瘤生长。对Notch信号激活和对照小鼠的巨噬细胞表达谱进行检测，发现乳酸转运体家族多个成员表达发生改变。据此，本研究拟进一步阐明Notch信号通过乳酸转运体参与TAM极化和功能的调控作用；探究乳酸对TAM功能的影响及在肿瘤进展中作用和机制。本研究有望从乳酸代谢角度完善Notch信号调控TAM极化和功能的分子网络，为肿瘤治疗提供新靶点，具有重要理论意义和潜在应用价值。

Macrophages are important component of innate immune system, which possess different polarization status responding to different inflammatory stimuli. The polarizations and function switch of tumor-associated macrophages (TAMs) participate into each stage of tumor development. Many factors in tumor microenvironment regulate TAMs polarization and function remodeling. The Warburg effect of tumor cells leads to lactate accumulation in microenvironment, which facilitates M2 polarization of TAMs to further promote angiogenesis and tumor progression. Our previous studies have found that forced activation of Notch signal could re-educate TAMs to M1 polarization with anti-tumor phenotype and improve immune microenvironment to inhibit tumor growth. Using next generation sequencing for further exploring the mechanism of Notch signaling regulation macrophage polarization, we found that expressions of several members of lactate transporters family showed significant difference between Notch activated macrophages and control group. Based on the above data, this study will clarify the regulation effect of Notch signal on TAMs polarization and function through lactate transporters, and explore the roles and mechanisms of lactate on modulating TAMs function and tumor progression. This project should replenish the network of Notch signal modulating TAMs polarization and function from the perspective of lactate metabolism, and provide new targets for tumor therapy, which has important theoretical significance and potential application value.