MED12缺失介导卵巢癌细胞免疫逃逸作用及其机制

介导肿瘤免疫逃逸的原因复杂，机制不清。我们发现在MED12缺失的肿瘤组织中，PD-L1高表达，浸润淋巴细胞减少，提示MED12缺失可能介导肿瘤免疫逃避，但机制不详。本研究拟以CRISPR/cas9或基因沉默技术建立敲除或低表达MED12的多种人和小鼠卵巢癌细胞模型，比较研究野生型MED12/wt和MED12/KO肿瘤细胞的人源化小鼠或小鼠的肿瘤移植瘤模型的肿瘤组织浸润淋巴比例、活性及其对PD-1/PD-L1抗体治疗的疗效。同时，以单细胞组学技术等方法比较研究MED12缺失对肿瘤细胞的抗原表达、共刺激因子及趋化因子表达、局部免疫微环境细胞组成（肿瘤细胞、成纤维细胞、淋巴细胞等）及免疫相关基因表达谱特征的影响。发现及验证介导肿瘤免疫逃避的关键分子，揭示MED12缺失在肿瘤免疫逃逸中的作用及其规律，阐明其机制，为 PD-1/PD-L1检查点抑制剂治疗卵巢癌的应用提供新思路、新策略。

The mechanism of tumor immune escape is complex and much remains unclear. We found that in MED12-deficient tumor tissues, PD-L1 is highly expressed and infiltrating lymphocytes are reduced, suggesting that MED12 deletion may contribute to tumor immune escape. This study intends to use CRISPR/cas9 or gene silencing technology to establish a variety of human and mouse ovarian cancer cell models with knockout or low expression of MED12, and establish their xenograft model in nude mice and humanized model NCG mice. To study the gene expression profiles or activity of TIL, M2 and cancer associated fibroblast (CAF) cells, and predict response to anti-PD-1/PD-L1 antibody treatment. Moreover, we will use single cell omics technology to study the effect of MED12 deletion mutation on expression of antigens, co-stimulatory factors and chemokines and on tumor cell composition (tumor cells, fibroblasts, lymphocytes, etc.). Our study aims to demonstrate the regulatory mechanism of MED12 deletion in tumor immune escape, to screen and identify the key regulatory genes, and provide new strategies for the application of PD-1/PD-L1 checkpoint inhibitors in the treatment of ovarian cancer.