西达本胺靶向RNA剪切复合体诱导巨噬细胞重编程及其在抗T/NK细胞淋巴瘤中的作用研究

T/NK细胞淋巴瘤预后较差，疗效亟待提高。西达本胺与同类挽救治疗药物药物相比，具有最长的总生存期数据，其机制未明。我们前期研究发现西达本胺通过原有靶点组蛋白去乙酰化酶非依赖途径促进肿瘤相关巨噬细胞（TAMs）向经典活化型（M1）极化；生物素-pulldown和高通量质谱分析发现西达本胺与RNA剪切因子SYNCRIP结合，参与调控TAMs表型。本项目拟通过体外实验、临床样本检测和定向敲除巨噬细胞SYNCRIP动物模型明确SYNCRIP与TAMs重编程的相关性；应用RNA测序、RNA免疫共沉淀和可变剪切分析技术多渠道探讨西达本胺影响SYNCRIP参与RNA剪切过程，促进TAMs向M1重编程的分子机制；多维度证实西达本胺靶向SYNCRIP对T/NK细胞淋巴瘤生长的抑制作用；最后在多种动物模型上评估西达本胺和免疫检查点阻断剂的单药/联合的抗肿瘤作用，为探索T/NK细胞淋巴瘤治疗提供新靶点和新策略。

T/NK-cell lymphoma is a poor prognosis lymphoma subtype and the efficacy improvement is urgently needed. Compared with other salvage therapeutic agents, chidamide achieved the longest overall survival, but the underlying mechanism was unclear. In our former research, we found that chidamide could promote tumor associated macrophages (TAMs) to anti-tumor M1 phenotype through its original target histone deacetylase independent pathway. We also found chidamide could combine with RNA splicing factor SYNCRIP regulating TAMs polarization with biotin-pulldown assay and high throughput mass spectrometry analysis. This project intends to clarify the correlation between syncrip and TAMs reprogramming by in vitro experiment, clinical sample detection and targeted knockout macrophage syncrip animal model; to explore the molecular mechanism of chidamide affecting syncrip participation in RNA splicing process and promoting TAMs reprogramming to M1 by RNA sequencing, RNA immunoprecipitation and alternative splicing analysis; to confirm chidamide targeting syncrip in multiple dimensions inhibition on T / NK cell lymphoma growth. Finally, the single / combined antitumor effects of chidamide and immunocheckpoint inhibitor were explored on a variety of animal models to provide new targets and new strategies of T / NK cell lymphoma.