髓系来源抑制细胞(MDSCs)是促使肿瘤发生免疫逃逸的关键免疫抑制细胞之一。肿瘤微环境中炎性白介素是MDSCs产生和发挥功能的关键外在因素，但其信号网络如何影响MDSCs产生和功能尚不清楚。我们利用条件性基因剔除小鼠建立肝肿瘤模型时发现，Notch信号剔除导致肿瘤明显增大，同时伴随MDSCs增多。结合文献和我们前期报道Notch信号对关键促炎白介素信号下游的JAK/STAT和NF-κB途径等都具有正、反两种调节模式，提示：Notch 信号可能通过调控白介素信号参与MDSCs形成和功能。本课题拟利用多种基因修饰小鼠，进一步观察和明确Notch阻断/激活后肿瘤生长与MDSCs及关键白介素信号的关系；确定Notch信号通过白介素信号调控MDSCs形成和功能的关键结点；确定干预MDSCs抑制肿瘤生长的靶点。本研究有望揭示Notch-白介素信号调控MDSCs产生和功能的分子机制，并建立新的干预策略。

Myeloid-derived suppressor cells (MDSCs) are immune suppressive immature myeloid cells that play an important role in tumor initiation and subsequent growth, invasion and metastasis. Proinflammatory interlukins (ILs )are key extrinsic factors for the generation and function of MDSCs. However, how the interleukin receptor-mediated signaling network effects on the generation and function of MDSCs remains unclear. With a macrophage-specific RBP-J deficiency mouse model, we have found that tumor grows faster in liver of RBP-J deficient mice than in wild type mice, accompanied with the increased tumor associated macrophages (TAMs), while the number of MDSCs increased too. Our previous studies had shown that Notch signaling can regulate both JAK/STAT and NF-κB signaling through positive and negative loop in ILs-mediated chronic inflammation, suggesting that Notch signaling might be a critical intrinsic factor to promote the expansion and function of MDSCs through the proinflammatory ILs-mediated signaling. In the current project, we intend to clarify the contribution of Notch-interleukin receptor-mediated signaling to the expansion and function of MDSCs involved in tumor development by using myeloid-specific RBP-J deficient or Notch signal-activated mice. We will also reveal the key regulation points between Notch signaling and interleukin receptor-mediated pathways for the accumulation and function of MDSCs. Furthermore, we will look for the strategies to intervene with the generation and function of MDSCs by targeting Notch and interleukin receptor-mediated pathways. Our study will explore the molecular mechanism of regulation network of Notch-interleukin receptor-mediated pathways on the generation and function of MDSCs , and finally provide new strategies and targets for the intervention of MDSCs in cancer treatment.