色氨酸代谢在间充质干细胞促乳腺癌转移中的机制研究

Mesenchymal stem cells (MSCs) are a major component of tumor microenvironment. Our previous reports have demonstrated inflammatory cytokines-activated MSCs could promote tumor progression and metastasis. MSCs could inhibit tumor-infiltrating T cells and thus impairing tumor immunity and promoting tumor growth through producing indoleamine 2,3-dioxygenase (IDO). The inhibitor of IDO, 1-MT, could inhibit tumor growth efficiently. Besides, MSCs also recruit macrophages and neutrophils, which contribute to tumor progression and metastasis, through secreting CCL2, CXCL1 and CXCL2. However, it remains elusive about the detailed mechanisms underlying the interaction between MSCs and immune cells in promoting tumor metastasis. Our preliminary study has found that IDO could inhibit T cell proliferation, thus impairing T cell-mediated tumor immunity. It could also affect the activity of macrophages and neutrophils through IDO-catalyzed tryptophan metabolite. In this project, we aims to find the new interaction between tryptophan metabolism and tumor metastasis through blocking IDO-catalyzed tryptophan metabolism pathway. Moreover, to understand the interaction between MSCs and immune cells in promoting tumor metastasis, we will explore the effect of tryptophan metabolites on immune cells. This project will provide us with new therapeutic target of tumor, which will fulfill the theoretic foundation to optimize the clinical application of MSCs in tumor therapy.

间充质干细胞（MSCs）是乳腺癌等肿瘤微环境的重要组成成分。我们已经证明了MSCs在炎症因子刺激后可以促进肿瘤的生长和转移。MSCs通过吲哚胺2,3-双加氧酶（IDO）抑制肿瘤中浸润的T细胞，从而促进肿瘤生长；在加入IDO抑制剂1-MT后可有效抑制肿瘤生长。另外，MSCs通过分泌CCL2、CXCL1和CXCL2，招募巨噬细胞和中性粒细胞等，也可促进肿瘤的生长和转移。然而MSCs和免疫细胞之间的相互作用，及其如何促进肿瘤转移的具体机制仍不清楚。我们前期研究已经发现，IDO催化的色氨酸（Trp）代谢产物也能调控巨噬细胞和中性粒细胞。本课题将利用乳腺癌转移小鼠模型，通过阻断MSCs中色氨酸代谢通路，明确色氨酸代谢在MSCs促进乳腺癌转移中的作用；并探究在色氨酸代谢产物作用下，绘制乳腺癌转移中MSCs对免疫细胞的作用机制图谱，发现新的乳腺癌治疗靶点，为临床治疗乳腺癌提供理论依据。

间充质干细胞（MSCs）是乳腺癌等肿瘤微环境中的重要组成成分。在炎症因子刺激下，MSCs通过吲哚胺2,3-双加氧酶（IDO）抑制肿瘤中浸润的免疫细胞，从而促进肿瘤生长。IDO是调控色氨酸代谢的限速酶。本项目从MSCs、色氨酸代谢、免疫细胞和乳腺癌肺转移出发，分别研究了MSCs中色氨酸代谢对免疫细胞的作用，MSCs对乳腺癌肺转移的作用，以及色氨酸代谢产物对MSCs的影响。结果表明IDO介导的色氨酸代谢能抑制免疫细胞的炎症反应。MSCs通过CCL5-CCR5招募巨噬细胞，从而促进乳腺癌的肺部转。色氨酸代谢产物可改变MSCs趋化因子及细胞因子的表达，提示了色氨酸代谢参与MSCs对免疫细胞的招募。本项目揭示了色氨酸代谢一方面能介导MSCs治疗炎症性肠病（IBD）等自身免疫疾病；另一方面通过免疫细胞促进乳腺癌肺部转移，其详细作用机制正在研究中。本项目资助下在Stem Cell Research and Therapy上发表相关论文。