经典霍奇金淋巴瘤中组蛋白去乙酰化酶抑制剂对PD-L1表达的调控和影响肿瘤微环境免疫功能的机制研究

There is still no consensus in the treatment for classical Hodgkin lymphoma (cHL) after its relapse. Immune checkpoint inhibitors bring hope to such patients; However, the complete remission rate is not high. Our research group suggested that MGCD0103, one of the histone deacetylase inhibitors (HDACIs), could make the expression of PD-L1 rise in HRS (Hodgkin and Reed Sternberg) cells. HDACIs could enhance not only the function of immune cells in microenvironment but also therapeutic effects of PD-1 inhibitors; hence, it was a hypothesis that MGCD0103 and PD-1 inhibitors had synergistic effects that could extremely strengthen the function of immune cells. PD-L1, PD-1, MHC-I/II, TBET, IFNγ, FoxP3 and other indexes were assayed in the patients with cHL before and after the relapse, the pathological data of which were analyzed relevantly with their clinical data. The expression of PD-L1 in HRS cells and the regulatory mechanism on its gene level were explored. Lymphocytes and tumor cells co-culture techniques and established animal models were employed to research effects of HDACIs and/or Anti-PD-1 on the immune function of each cell component of cHL in microenvironment. The aim of this research was to provide critical parameters and clear theories and practical instructions for the clinical trials design of HDACIs combined with PD-1 inhibitors, so as to lay a foundation for resolving the treatment problem of cHL fundamentally.

经典型霍奇金淋巴瘤(classic Hodgkin lymphoma，cHL)复发后的治疗还没有共识, 免疫检测点抑制剂疗效较好但完全缓解率不高。本组前期研究显示，组蛋白去乙酰化酶抑制剂（HDACIs）MGCD0103能使cHL细胞PD-L1表达升高，结合文献报道HDACIs增强肿瘤微环境免疫细胞功能并增强PD-1抑制剂治疗效果，推测HDACIs和PD-1抑制剂有协同效应。我们将用免疫组织化学法、Western blot测定复发cHL患者PD-L1、MHC-I/II、TBET、IFNγ和FoxP3等指标并研究临床相关性，用ChIP等技术研究PD-L1表达基因转录调控机制，建立体内外肿瘤模型研究HDACIs和/或Anti-PD-1对cHL微环境各免疫细胞功能的影响。为HDACIs联合PD-1抑制剂的临床研究设计提供关键参数和清晰的理论指导，为根本解决复发cHL治疗问题打下基础。

经典型霍奇金淋巴瘤(classic Hodgkin lymphoma，cHL)复发后还没有治疗共识, 免疫检测点抑制剂治疗给这部分患者带来希望，但完全缓解率不高，作用机制还不清楚。本课题组研究显示，组蛋白去乙酰化酶在cHL中表达具有特征性，和治疗的预后有关；组蛋白去乙酰化酶抑制剂（HDACIs）MGCD0103 能使cHL 细胞PD-L1表达升高，HDACIs 增强肿瘤微环境免疫细胞功能并提高PD-1 抑制剂治疗效果，显示HDACIs 和PD-1 抑制剂有协同效应。我们测定了复发cHL 患者PD-L1、PD-1、MHC-I/II、Bcl-2和p65 等指标并研究了临床相关性；我们正在构建cHL 微环境各细胞成分的免疫共培养体系，检查HDACIs 和/或Anti-PD-1 对免疫微环境细胞功能影响。为HDACIs 联合PD-1抑制剂的临床研究设计提供关键参数和清晰的理论、实践指导，使我们在该领域的实践和理论水平走在国际同行的前沿，为根本解决cHL 的治疗问题打下基础。