MLL4/COMPASS复合体在肿瘤免疫逃逸中的功能与作用机制研究

靶向免疫检查点的抑制剂在临床上得到了广泛运用，然而，仅有部分肿瘤类型和某一肿瘤类型中的部分病人能从中获益，其主要原因是肿瘤中CD8+ T细胞浸润和/或活化较少。目前，肿瘤中CD8+ T细胞浸润、活化以及失活的分子机制仍不清楚，阻碍了免疫检查点抑制剂在临床治疗中的普及。我们前期的研究发现，转录增强子H3K4甲基转移酶MLL4/COMPASS复合体的缺失可以促进肿瘤微环境中CD8+ T细胞的浸润与活化。 机制研究发现MLL4缺失激活了肿瘤细胞中的焦亡和一型干扰素信号通路。基于以上的结果，本项目将进一步探究MLL4/COMPASS复合体缺失激活焦亡和一型干扰素信号通路的机制，以及二者在MLL4介导的肿瘤免疫逃逸中的作用，以期为抗肿瘤免疫应答的表观遗传机制提供新的认识，为临床上治疗抵抗免疫检查点抑制剂治疗的病人提供新的策略。

Inhibitors that target immune checkpoints have been widely used in clinical practice. However, only some patients can benefit from them. The main reason behind the low efficacy of immune checkpoint blockade therapies is insufficient infiltration and/or activation of CD8+ T cells in tumors. At present, the molecular and cellular mechanisms underlying the infiltration、activation and exhaustion of CD8+ T cells remain incompletely understood, thus hindering the broad application of this therapeutic strategy in tumor treatment. Our previous research found that deletion of MLL4/COMPASS complex, the H3K4 monomethyltransferase for transcriptional enhancers can promote the infiltration and activation of CD8+ T cells in the tumor microenvironment. Further mechanistic studies by RNA-seq of ex vivo tumor cells revealed that MLL4 ablation leads to activation of both pyroptosis and type I interferon signaling pathways in tumor cells. This project aims to further study how pyroptosis and type I interferon signaling pathways are activated by MLL4/COMPASS depletion and explore their potential roles in the immune escape of tumor cells mediated by MLL4/COMPASS. Findings from this project will provide new insights into the epigenetic mechanisms of anti-tumor immunity and possibly find out new clinical treatment strategies for the patients who are refractory to immune checkpoint blockade therapies.