Setdb2通过尿酸合成途径关键酶XOR调控TAM极化在肿瘤发生中的作用和机制研究

肿瘤相关巨噬细胞（TAM）与非小细胞肺癌发生密切相关，改变代谢调控TAM极化进而增强抗肿瘤免疫反应被视作新型治疗模式。组蛋白甲基转移酶Setdb2表观遗传调控尿酸合成途径关键酶XOR，然而Setdb2影响TAM极化的机制尚不明确。我们前期研究发现，非小细胞肺癌TAM低表达Setdb2、高表达XOR，体外敲低Setdb2使XOR上调且巨噬细胞呈M2表型，体内验证Setdb2低表达巨噬细胞促进肿瘤发生，XOR抑制剂可部分逆转该现象。由此我们提出Setdb2通过尿酸合成途径调控TAM极化的假说。本研究拟一、收集临床标本分析Setdb2和XOR在TAM中的表达与癌症发生和预后的关系；二、体内实验探究TAM中Setdb2对肿瘤发生的影响；三、体外实验阐明Setdb2对TAM代谢谱和免疫功能的改变；四、确定Setdb2调控TAM极化的具体分子机制。本研究将为寻找新的非小细胞肺癌免疫治疗检查点奠定基础。

Tumor-associated macrophage (TAM) is critically involved in the tumorigenesis of Non-small cell lung cancer. Changing the polarization phenotype of TAM by metabolic intervention has been regarded as a novel treatment technique, ultimately enhancing anti-tumor immune response. Setdb2 is a histone methyltransferase that is correlated with the epigenetic modulation of the expression of xanthine oxidoreductase (XOR), a key enzyme of uric acid synthesis pathway. It remains obscure how Setdb2 regulates the phenotype and function of TAM. Our previous study revealed that Setdb2 was down-regulated, meanwhile XOR was up-regulated in TAM compared with macrophage from non-cancerous tissue. Knockdown of Setdb2 in macrophage increased the expression of XOR and M2 type macrophage markers. We also identified inhibition of Setdb2 in TAM promoted tumor activity in mice, and XOR inhibitor could partly reverse this phenomenon. Based on the results above, we speculate that Setdb2 interference the polarization of TAM by epigenetic regulation of XOR. Our present explore will (1) analyze the relationship between clinical outcome and expression of Setdb2 or XOR in TAM of Non-small cell lung cancer, (2) study the function of Setdb2 in tumorigenesis in vivo, (3) clarify the influence of Setdb2 on the metabolism and anti-tumor immunity of TAM, (4) elucidate the regulatory mechanism of Setdb2 on XOR expression. Our project will provide a theoretical basis for novel immune checkpoint for Non-small cell lung cancer.