Mechanisms of immunomodulation with epigenetic therapy

项目摘要/摘要 针对程序性细胞死亡蛋白1(PD-1)或其配体的免疫检查点抑制物(ICI)已经产生 一些癌症的临床益处前所未有，但在包括胰腺癌在内的其他癌症中却失败了 (PDA)。PDA表现为低T细胞浸润和大量免疫抑制细胞类型，包括髓系细胞- 衍生抑制细胞(MDSCs)。逆转固有免疫抑制的联合方法 PDA的生物学将是将PDA转变为ICI敏感肿瘤类型的关键。我们的团队和其他人报告说 表观遗传疗法可以影响肿瘤和肿瘤微环境(TME)中的其他细胞， 包括免疫细胞和基质细胞。我们报道了组蛋白去乙酰化酶抑制剂(HDACi)内抑素 调节髓系来源的抑制细胞(MDSCs)，导致较少的免疫抑制群体。我们 已经将这些临床前发现转化为正在进行的Eninostat与PD-1联合的临床试验 抑制剂nivolumab，我们在转移性PDA患者中观察到了多种临床反应。这个 目前的建议建立在我们现有的临床前数据的基础上，以回答关于如何 表观遗传调节疗法对TME进行重新编程，以进行系统免疫治疗。我们假设HDACi 治疗可以调节PDA TME中的多种炎性细胞、间质细胞和肿瘤细胞，转化PDA肿瘤 从免疫性癌症到免疫反应性癌症。我们将首先评估HDACi修改的路径 我们的临床前研究结果进一步确定了HDACi改变的特定途径。这项工作将具体地 测试从我们的初步数据中产生的假设，即STAT3调节介导Eninostat对 MDSC通过调节多条炎症途径发挥作用，从而产生抗肿瘤作用 同时给予抗PD1治疗。我们还将扩大对免疫调节作用的研究 HDACi用于评估恩替诺斯特对从以下来源接收信号的集中免疫人群的影响 MDSCs。我们将使用我们的临床前模型来检验这样一种假设，即Eninostat发现与突变相关的 单独或联合系统性增强抗肿瘤免疫的胰腺癌新抗原 免疫疗法。我们将使用我们独特的生物标本来确认我们的临床前发现 正在进行的内抑素联合抗PD1治疗PDA的临床试验正在进行中，正在进行一系列的活检 基线，在内抑素单一治疗和联合治疗后，允许评估免疫 HDACI单独及与ICI联合应用对TME的影响。此外，我们希望在我们的临床基础上 通过研究其他新药的合理组合，提供Eninostat和nivolumab的经验 为未来的治疗试验奠定临床前基础。

Project Summary/Abstract Immune checkpoint inhibitors (ICI) targeting programmed cell death protein 1 (PD-1) or its ligand have produced unprecedented clinical benefit for some cancers but have failed in others including pancreatic adenocarcinoma (PDA). PDAs display low T cell infiltration and high numbers of immunosuppressive cell types including myeloid- derived suppressor cells (MDSCs). Combination approaches that reverse the intrinsic immunosuppressive biology of PDA will be key to converting PDA into an ICI-sensitive tumor type. Our group and others reported that epigenetic therapies can influence both tumors and other cells in the tumor microenvironment (TME), including immune and stromal cells. We reported that the histone deacetylase inhibitor (HDACi) entinostat modulates myeloid-derived suppressor cells (MDSCs), resulting in a less immunosuppressive population. We have translated these preclinical findings into an ongoing clinical trial of entinostat in combination with the PD-1 inhibitor nivolumab, on which we have observed multiple clinical responses in metastatic PDA patients. The current proposal builds upon our existing pre-clinical data to answer important mechanistic questions as to how epigenetic modulatory therapies reprogram the TME for systemic immunotherapy. We hypothesize that HDACi therapy can modulate multiple inflammatory, stromal and tumor cells in the PDA TME, converting PDA tumors from immune excluding into immune responsive cancers. We will first evaluate HDACi modified pathways from our preclinical findings to further identify specific pathways that are altered by HDACi. This work will specifically test the hypothesis generated from our preliminary data that STAT3 modulation mediates entinostat’s effects on MDSC function through regulation of multiple inflammatory pathways, resulting in the antitumor effect seen when given in combination with anti-PD1 therapy. We will also expand our investigation of the immunomodulatory effects of HDACi to evaluate the effect of entinostat on focused immune populations that receive signals from MDSCs. We will use our preclinical models to test the hypothesis that entinostat uncovers mutation-associated pancreatic cancer neoantigens that can augment antitumor immunity alone or in combination with systemic immunotherapies. We will confirm our preclinical findings using our unique biospecimens collected from our ongoing clinical trial of entinostat in combination with anti-PD1 therapy in PDA that is banking serial biopsies at baseline, after entinostat monotherapy and after combination therapy, allowing assessment of the immune impact of HDACi alone and in combination with ICI on the TME. In addition, we hope to build upon our clinical experience with entinostat plus nivolumab by studying rational combinations of additional novel agents, providing a preclinical basis for future therapeutic trials.