DNA损伤特异性激活NF-κB/HLA-DRB6/CD1d，促进自然杀伤T细胞对白血病干细胞的清除作用和机制

损伤DNA是多数抗癌药物共同的机制，肿瘤细胞DNA损伤后可特异性激活NF-κB/PARP1通路，从而重塑肿瘤免疫微环境, 最终影响免疫细胞对肿瘤杀伤效果。但是，NF-κB被DNA损伤激活后重塑肿瘤免疫微环境的特异性新靶点是什么？我们前期研究表明DNA损伤后NF-κB/RELA可调控CD1d的转录，而且可能是由长链非编码RNA（LncRNA）HLA-DRB6介导的，从而增强自然杀伤T（NKT）细胞毒作用，减少人AML 干/祖 细胞集落形成。由此，我们设想NF-κB/HLA-DRB6/CD1d可能形成通路精确调节NKT细胞活性，促进AML干细胞清除。因此本课题拟从分子、细胞和动物水平探讨该通路各个分子之间具体作用位点及机制，以期充分阐明NF-κB被DNA损伤特异性激活后参与NKT细胞免疫杀伤的分子机制，以及NKT激活剂和PARP1抑制剂联合使用能否协同重塑肿瘤免疫微环境，清除AML干细胞。

DNA damage is the common mechanism of most anticancer drugs. After DNA damage, tumor cells can specifically activate NF-κB/PARP1 pathway, thus reshaping tumor immune microenvironment, and ultimately affecting the cytotoxicity of immune cells to tumor cells. However, what are the specific new targets for NF-κB to remodel tumor immune microenvironment after being activated by DNA damage? Our previous studies showed that NF-κB/RELA can regulate the transcription of CD1d after DNA damage, and it may be mediated by long non coding RNA (LncRNA) HLA-DRB6, so as to enhance the cytotoxicity of natural killer T (NKT) cells and reduce the colony forming units of human AML stem/progenitor cells. Therefore, we hypothesized that NF-κB/HLA-DRB6/CD1d may form a pathway to precisely regulate the activity of NKT cells and promote the clearance of AML stem cells. Therefore, this study intends to explore the specific action sites and mechanisms among the molecules of this pathway at the molecular, cellular and animal levels, in order to thoroughly clarify the molecular mechanism of NF - κ B participating in the immunokilling of NKT cells after being specifically activated by DNA damage, and whether the combination of NKT activator and PARP1 inhibitor can cooperate to reshape the tumor immune microenvironment, so as to completely eliminate AML stem cells.