肺癌中lncRNA PVT1对PMN-MDSCs免疫抑制功能的促进作用及机制研究

The immunosuppression induced by myeloid derived suppressor cells (MDSCs) plays a crucial role in tumor escape. And long noncoding RNA (lncRNA) has been indicated as a core regulator of cell biology. However, the effect and regulatory mechanism of lncRNA on the immunosuppressive function of MDSCs remain unclear. Our preliminary studies indicated that knockdown of lncRNA PVT1 could downregulate the immunosuppression of PMN-MDSCs derived from tumor tissue of lung cancer. Furthermore, knockdown of lncRNA PVT1 could downregulate the expression of myelocytomatosis oncogene (MYC). Additionally, MYC has been demonstrated to enhance the immunosuppression of PMN-MDSCs in abundant studies. Thus, we hypothesized that lncRNA PVT1 can increase the immunosuppression of PMN-MDSCs by regulating MYC. Therefore, we attend to further explore the role of lncRNA PVT1 in the immunosuppression of PMN-MDSCs in LLC mouse model and lung cancer patients. This project aims to deepen the understanding of lncRNA PVT1 in regulating the function of PMN-MDSCs, and provide sufficient scientific basis for the immunotherapy of lung cancer.

髓源抑制性细胞（MDSCs）引起的免疫抑制环境是造成肺癌等恶性肿瘤免疫逃逸的重要机制之一。长链非编码RNA（lncRNA）在调控细胞生物学行为中发挥重要作用，目前lncRNA对MDSCs免疫抑制功能的调控机制尚不明确。申请人前期研究发现：敲减多核型MDSCs（PMN-MDSCs）中lncRNA PVT1，能够下调PMN-MDSCs的免疫抑制功能，伴有细胞中骨髓细胞瘤癌基因（MYC）的降低。早先研究证实MYC能够促进PMN-MDSCs的免疫抑制功能。据此我们提出科学假说：lncRNA PVT1通过调控MYC分子，增强PMN-MDSCs的免疫抑制功能，进而促进肺癌发展。申请人拟在细胞、动物及临床标本中确认lncRNA PVT1对PMN-MDSCs免疫抑制功能的调控作用及具体机制，进一步了解肺癌免疫逃逸机制，为肿瘤免疫治疗提供重要的科学理论依据。

髓源抑制性细胞（MDSCs）引起的免疫抑制环境是造成肿瘤免疫逃逸的重要机制之一。长链非编码RNA（lncRNA）作为关键性的免疫调控分子，在肿瘤免疫中发挥重要作用。但lncRNA对MDSCs免疫抑制功能的调控机制尚未明确。本项目通过构建肺癌小鼠移植瘤模型，明确肿瘤缺氧微环境诱导的lncRNA PVT1对PMN-MDSCs免疫抑制功能的调控作用：（1）肿瘤缺氧微环境通过上调HIF-1a水平，促进PMN-MDSCs中lncRNA PVT1的表达；（2）lncRNA PVT1通过在转录水平/转录后水平上调PMN-MDSCs中c-Myc分子水平，增强PMN-MDSCs的免疫抑制功能，进而加快肿瘤的发展进程。通过本项目的研究，我们明确lncRNA PVT1调控PMN-MDSCs功能的分子机制，为肿瘤的免疫治疗提供实验理论依据。