低剂量西达本胺与低剂量阿扎胞苷协同调节GVHD/GVT效应的免疫作用机制

在控制移植物抗宿主病（GVHD）的同时增强移植物抗肿瘤（GVT）效应,是骨髓移植领域的研究热点。国外最新研究发现，去甲基化药物阿扎胞苷和组蛋白去乙酰化酶抑制剂（HDACi）均可促进调节性T细胞扩增而减轻GVHD。低剂量阿扎胞苷通过重激活抑癌基因，诱导肿瘤细胞重编程而“改邪归正”；与低剂量HDACi联合，提高组蛋白乙酰化，促进DNA去甲基化而协同强化抗肿瘤免疫，是抗肿瘤表观遗传药物与肿瘤免疫治疗有机结合的创新体现。西达本胺是新一代HDACi，既可通过表观遗传修饰抑制肿瘤细胞增殖，又可上调干扰素相关信号通路，增强T细胞对肿瘤的识别和杀伤能力。申请人曾证实干扰素受体信号通路是分离GVHD/GVT效应的一个关键靶点，我们假设联用西达本胺与阿扎胞苷(均低剂量)对异基因骨髓移植可能有益。拟继续以相关小鼠移植模型为平台，探究二药联用对GVHD/GVT的影响，揭示其分离GVHD/GVT的免疫作用机制。

The enhancement of graft versus tumor (GVT) effect while controlling graft versus host disease (GVHD) is a research hotspot in the field of allogeneic bone marrow transplantation (allo-BMT). The latest findings demonstrated that both demethylation drug Azacitidine（AZA） and histone deacetylase inhibitor (HDACi) can promote the expansion of Treg cells and alleviate GVHD. Low-dose AZA has been shown to “correct” the biological behavior of tumor cells by reactivating tumor suppressor genes and inducing reprogramming of tumor cells. The combination of low-dose AZA and low-dose HDACi is a novel strategy for cancer therapy reflecting the connection of epigenetics and immunotherapy, which can up-regulate histone acetylation, promote demethylation of DNA and mediate enhanced anti-tumor immunity. As a new generation drug of histone deacetylation enzyme inhibitor, chidamide not only inhibits the proliferation of tumor cells by epigenetic modification, but also promote the ability of T cells to recognize and kill tumor cells through the up-regulation of the interferon-related signaling pathway. Based on the research results mentioned above, and the publication in which the applicant has already confirmed that the IFN-gamma receptor signal pathway is a key target for separating GVT effect from GVHD, we assume that the combination of low-dose chidamide with low-dose AZA may exert benefical effect during allo-BMT. We will continue to use the relevant transplantation mouse models to explore the effect of the above two drugs on the regulation of GVHD/GVT and confirm the immune mechanism of this therapeutic protocol.