组蛋白去乙酰化酶3调控B细胞淋巴瘤中PD-L1表达的分子机制及其治疗意义

The PD-1/PD-L1 signaling axis plays a critical role in tumor immune escape. Blockage of this pathway has exhibited effective therapeutic effect in many human cancers, including B cell lymphomas. It has been reported that pan-histone deacetylase inhibitor (HDACi) arguments the therapeutic efficacy of anti-PD-1/PD-L1 immunotherapy via up-regulation of PD-L1 expression on tumor cells, providing a theoretical basis for clinical combination of these strategies. However, there are eighteen isoforms of HDACs, many of which have been reported to be inhibited by pan-HDACi. Accordingly, clinical usage of pan-HDACi is associated with substantial adverse effects in patients. Therefore, identification of specific HDAC isoforms involved in PD-L1 expression and the corresponding HDAC inhibitors appears to be of paramount importance. Our preliminary data show that RGFP966, a specific HDAC3 inhibitor, increases PD-L1 expression in B-cell lymphomas. This project aims at elucidating the molecular mechanism by which HDAC3 regulates PD-L1 expression in B-cell lymphoma, as well as exploring the efficacy of combining HDAC3 inhibitor with anti-PD-1 antibody for the treatment of this disease and the associated mechanisms, providing a rational for combining HDAC3 inhibitor with PD-1 blockade in the future.

PD-1/PD-L1信号通路在肿瘤免疫逃逸过程中起到非常关键的作用，而阻断这条通路对许多肿瘤包括B细胞淋巴瘤具有明显的临床治疗效果。广谱组蛋白去乙酰化酶抑制剂通过提高肿瘤细胞上PD-L1的表达，促进抗PD-1/PD-L1免疫治疗的效果。然而，组蛋白去乙酰化酶有18种亚型，其中多种亚型都受到广谱组蛋白去乙酰化酶抑制剂影响。因此，在临床上使用广谱的组蛋白去乙酰化酶抑制剂将产生极大的副作用。鉴定有效调节PD-L1表达的组蛋白去乙酰化酶亚型及其特异性的抑制剂显得尤为重要。我们前期工作发现在B细胞淋巴瘤中，组蛋白去乙酰化酶3的特异性抑制剂RGFP966能够诱导PD-L1表达。本项目将深入研究组蛋白去乙酰化酶3调控PD-L1表达的分子机制，以及RGFP966协同PD-1抗体抑制体内肿瘤生长的效果和相关机制，为将来临床上联合使用这两种治疗手段治疗B细胞淋巴瘤提供理论根据。

组蛋白去乙酰化转移酶（HDAC）是被广泛研究的表观遗传调节蛋白，包含多种亚型。目前发现广谱的HDAC抑制剂能够杀伤B细胞瘤，并具有免疫调节作用，并用于多项临床试验。程序性死亡蛋白1 及其配体(PD-L1)信号通路是目前发现的关键肿瘤免疫逃逸机制之一，具体的调控机制未知。本课题主要研究调控B细胞淋巴瘤中调控PD-L1表达的HDAC亚型，以及相关的分子机制。 我们发现HDAC3特异性的抑制剂RGFP966能够诱导B淋巴瘤细胞死亡且上调PD-L1的表达。HDAC3抑制剂迅速增加PD-L1启动子区域的组蛋白乙酰化，并招募BRD4来促进其表达。机制上，HDAC3和其共抑制子SMRT通过BCL6被招募到PD-L1的启动子区域。此外，HDAC3抑制剂能够减少DNA甲基化酶1的蛋白水平来增加PD-L1转录。HDAC3抑制剂在小鼠体内肿瘤中树突状细胞的PD-L1水平。最后，我们发现HDAC3选择性抑制剂和PD-L1抗体联合使用在小鼠淋巴瘤模型中取得更好效果。 我们的工作鉴定HDAC3是PD-L1重要的表观遗传调节子，且提示联合这些抑制剂和抗PD-L1/PD-1抗体治疗B细胞淋巴瘤。