HDACi西达本胺调控STAT1提高PD-1抗体治疗NHL疗效的作用及机制研究

PD-1抗体治疗非霍奇金淋巴瘤（NHL）效果不佳的现状亟待解决。我们发现组蛋白去乙酰化酶抑制剂（HDACi）西达本胺可提高PD-1抗体治疗NHL的疗效，但机制不明。我们证明了西达本胺上调多种NHL中PD-L1表达，并首次揭示其促进肿瘤相关巨噬细胞（TAMs）的M1型极化，同时上游转录因子p-STAT1表达上调。由此推测：西达本胺可能特异性调控STAT1，上调PD-L1表达并促进TAMs向M1型极化，提升NHL免疫原性，提高PD-1抗体治疗NHL疗效。为验证此假设，本项目拟深入研究STAT1乙酰化分子机制，通过体内外实验阐明西达本胺经由STAT1乙酰化调控PD-L1表达及TAMs向M1极化的详细过程。本项目有望基于STAT1乙酰化调控作用阐明西达本胺免疫增敏新机制，为确立HDACi西达本胺联合PD-1抗体治疗NHL新策略提供更坚实的科学依据。

Although PD-1 immunotherapy is effective in the treatment of Hodgkin lymphoma, it hasn’t enough response in non-Hodgkin lymphoma (NHL). The aim of this study is to explore the drug which can effectively increase the response to PD-1 antibody treatment in NHL. Our pilot study found for the first time that histone deacetylase inhibitor (HDACi) chidamide can up-regulate the expression of PD-L1 in NHL and simultaneously facilitate M1 polarization of tumor-associated macrophages (TAMs) to enhance the ability of killing tumor cells and antigen presentation, and consequently increase the sensitivity of anti-PD-1 treatment in NHL. We also found that chidamide can up-regulate p-STAT1. Based on the findings of our pilot study, we propose a hypothesis that HDACi chidamide may up-regulate the expression of PD-L1, facilitate the polarization of TAMs to M1 by regulating the acetylation of STAT1, and subsequently improve the efficacy of PD-1 antibody in NHL. To validate our hypothesis, this study intends to explore the molecular mechanism of STAT1 acetylation by chidamide, and then study the effects of STAT1 acetylation on PD-L1 expression as well as the effects of TAMs to M1 polarization in vitro and vivo. The primary objective of our study is to verify the roles of HDACi chidamide in the activation of PD-1/PD-L1 pathway and the augmentation of the response to PD-1 immunotherapy in NHL. Finally, we highlight the potential scientific evidence of this work for the new strategy in the treatment of NHL by combining HDAC inhibitor chidamide with PD-1 antibodies. We also expected to clarify the new immunological priming mechanism of chidamide based on STAT1 acetylation.