KPNA2调控上皮性卵巢癌组织MDSCs浸润的机制与临床意义

Myeloid-Derived Suppressor Cells (MDSCs) are a population of immune cells that negatively regulate immune responses, which could promote tumor invasion and metastasis. Recently research has revealed that tumor could actively reshape the immune- microenvironment for its progression. We recently demonstrated that KPNA2 is a candidate oncogene in ovarian cancer that was closely related to MDSCs density, and found there was a positive position feedback between KPNA2 expressed and MDSCs density, which might contribute to the poor prognosis of patients. Based on these results, we will combine clinical sample analysis, animal model and experimental studies to:1) confirm the relationship between KPNA2 and MDSCs density, and its clinical significance;2) identify the cytokine and signal pathway recruiting MDSCs; 3) reveal the positive position feedback—KPNA2/MDSCs and the underlying mechanism; 4) use the inhibitor and neutralizing antibody of key molecules to interdict the above-mentioned loop, and discuss their potential as novel targets for cancer prevention and treatment. The conduction of this project will help explain the molecular mechanisms of how KPNA2 regulates ovarian cancer through suppressing the immune system, and provide new strategies by molecular targeted therapy combining biological therapy for ovarian cancer.

MDSCs是一群具有极强抑制功能的免疫细胞，能够促进肿瘤侵袭转移。新近研究显示肿瘤可主动重塑其局部免疫微环境组成以促进自身进展。我们课题组前期工作发现，上皮性卵巢癌的候选癌基因KPNA2表达水平与肿瘤中MDSCs浸润的密度相关，且KPNA2高表达的卵巢癌细胞与MDSCs之间可能存在正反馈的回路，提示不良预后。以此为基础，本课题拟结合体外实验、小鼠模型和临床样本：1）进一步证实KPNA2与MDSCs的相关性及其临床意义；2）鉴定出KPNA2调控MDSCs浸润的关键招募因子及相关激活通路；3）研究MDSCs-KPNA2反馈现象及作用机理；4）最后探讨利用抑制剂、中和抗体干扰KPNA2/MDSCs网络中的关键分子，阻断上皮性卵巢癌转移的可行性。本项目所得结果不仅有助于阐明KPNA2促进上皮性卵巢癌转移的新机制，还可望揭示调节免疫抑制的癌基因，为卵巢癌治疗提供个体化靶向结合免疫调节的新策略。

MDSCs是一群具有极强抑制功能的免疫细胞，能够促进肿瘤侵袭转移。新近研究显示肿瘤可主动重塑其局部免疫微环境组成以促进自身进展。我们课题组前期工作发现KPNA2是上皮性卵巢癌的不良预后因素。通过体内外实验，我们发现上皮性卵巢癌的KPNA2表达水平与肿瘤中MDSCs浸润的密度相关，且KPNA2高表达的卵巢癌细胞与MDSCs之间可能存在正反馈的回路，提示不良预后。过表达KPNA2卵巢癌细胞的肿瘤上清可以促进MDSCs的迁移，提示KPNA2高表达可能促进MDSCs的募集。与MDSCs共培养后，卵巢癌细胞的增殖、迁移、侵袭和细胞干性能力增强，对铂类敏感性减弱。转录组测序差异基因富集分析发现，KPNA2可能通过影响细胞因子和趋化因子的组蛋白和RNA甲基化关键因子，促进MDSCs的趋化能力，可望为提高卵巢癌的免疫治疗疗效提供新策略。