树突状细胞的PD-L1在肿瘤耐药中的功能与表达调控

耐药与复发是肿瘤化疗中所面临的一个难题。研究相关的机制对于改进当前的疗法具有重要意义。在某些情况下，PD-1/PD-L1信号能够介导肿瘤的耐药。然而，相关的机制目前尚不清楚。我们发现，不同的化疗药物（阿霉素或奥沙利铂）上调了不同细胞亚群（例如树突状细胞或肿瘤细胞）的PD-L1。而在某些模型中，免疫细胞上的PD-L1在抑制免疫反应中起到了比肿瘤细胞更加关键的作用。为了进一步揭示不同细胞在肿瘤耐药中的功能，我们制备了条件性PD-L1基因敲除小鼠，从而在不同细胞上特异性地敲除PD-L1。借助于工具小鼠与肿瘤模型，我们将研究PD-L1信号通路抑制免疫反应、介导肿瘤耐药的细胞与分子机制。同时，我们将筛选与鉴定树突状细胞中PD-L1基因的表达调控通路，并以这些通路为靶点筛选小分子抑制剂，应用于肿瘤的治疗。该研究将对临床上如何改进当前的化疗方法提供重要的参考，具有广阔的应用前景与重要的社会意义。

Drug resistance and tumor relapse are critical problems during chemotherapy. The mechanism studies of these questions are important for the improvement of current therapies. During chemotherapy, PD-1/PD-L1 signaling is able to mediate tumor resistance to chemotherapy. However, the mechanisms remain unknown. We found that different chemo-drugs (Doxorubicin or Oxaliplatin) upregulate PD-L1 on different subsets of cells (e.g., dendritic cells or tumor cells). In some tumor models, PD-L1 on immune cell plays a more important role to inhibit antitumor immune response. To further dissect the functions of PD-L1, we generated conditional PD-L1 knockout mice to specifically knockout PD-L1 on different cell populations. By using genetic-engineered mice and tumor models, we will study the cellular and molecular mechanisms by which PD-L1 inhibits immune responses and induces drug resistance. Furthermore, we will identify the regulatory mechanisms of PD-L1 expression in dendritic cells. We will select small molecule inhibitors targeting these pathways for tumor therapy. Our study will provide novel insights to how to improve the current chemotherapies in the clinic.