ALDH Inhibition as Modulator of Tumor Immunobiology

ALDH 抑制作为肿瘤免疫生物学的调节剂

• 批准号: 10392913
• 负责人: Ronald J Buckanovich
• 金额: $ 43.18万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392913
• 关键词: American; Anabolism; Binding; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Patient; Cancer Vaccines; Cell Death; Cell Proliferation; Cell physiology; Cells; Cellular biology; Cessation of life; Clinical; Data; Dendritic Cells; Disease; Down-Regulation; Enzyme Inhibitor Drugs; Enzymes; FOXP3 gene; Family; Family member; Generations; Genetic Transcription; Goals; Human; Immune; Immune Cell Suppression; Immune Tolerance; Immune system; Immunity; Immunobiology; Immunocompetent; Immunomodulators; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-12; Knock-out; LacZ Genes; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Modeling; Molecular; Mucin 1 protein; Mus; NR4A1 gene; Necrosis; Nuclear Receptors; Patients; Pattern; Pharmacology; Phenotype; Production; RXR; RXRA gene; Regulatory T-Lymphocyte; Reporter; Resistance; Retinoic Acid Receptor; Role; Signal Transduction; T cell differentiation; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Transgenic Mice; Tretinoin; Tumor Antigens; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Up-Regulation; Vaccines; Woman; aldehyde dehydrogenases; cancer cell; cancer immunotherapy; cancer therapy; cell type; checkpoint therapy; cytokine; exhaustion; immune checkpoint blockade; in vivo; inhibitor; knock-down; mortality; neoplasm immunotherapy; neoplastic cell; new therapeutic target; novel; novel strategies; novel therapeutics; ovarian neoplasm; receptor; response; stemness; therapeutic target; therapy resistant; transcription factor; transcriptome sequencing; transdifferentiation; tumor

Ovarian cancer (OvCa) is a deadly disease ranking 5th in cancer deaths in women, with the 3rd highest mortality to incidence ratio of all cancers. With patient overall survival not significantly changed for several decades, there is a clear unmet clinical need to develop new therapies for OvCa. Aldehyde dehydrogenase-1A enzymes (ALDH1A) represent a therapeutic target for OvCa. ALDH1A enzymes are upregulated in ovarian cancer initiating cells (CIC) and mediate the biosynthesis of retinoic acid (RA), to regulate numerous cellular processes. We recently identified a novel ALDH1A family inhibitor (ALDHi). Our preliminary data indicate that ALDHi treatment of cancer cells and immune cells have opposite effects, both of which could promote anti- tumor immunity. ALDHi treatment of CIC induces an RA and transcription- dependent necroptotic cell death, potentially related to altered function of the RA transcription partner NR4A1. This ALDHi-induced CIC death is associated with the release of Damage Associated Molecular Patterns (DAMPs) and other inflammatory mediators. In contrast, ALDHi treatment is associated with enhanced proliferative response of both dendritic cells (DC) and CD8+ T cells. Our overarching hypothesis is that ALDHi can act as an immune modulator and can be used to enhance immunotherapeutic approaches in OvCa. To test our hypotheses, we propose the following specific aims: SA1: To identify the RA receptors and downstream factors that drive ALDHi induced CIC necrosis and to determine whether ALDHi-induced CIC necroptosis is inflammatory cell death. We propose to test the role of individual RA receptors RAR/RXR and NR4A1 co-receptor in ALDHi-mediated CIC death and evaluate the impact of ALDHi/NR4A1 on CIC release of inflammatory mediators and this stimulation of an anti- tumor T cell response. Next, we will, in SA2: Assess the impact of ALDHi on host DC and T cells. As RA can regulate the differentiation of T cells and DC, we will use reporter mice to evaluate the role of ALDHi on disruption of RA/NR4A1 signaling and DC and T cell biology in vitro and in vivo. We will evaluate the capacity of DC to differentiate into IL-12 producing DC1, and CD4 T helper cell subsets differentiation with focus on the Th17/Treg trans-differentiation. Finally, our preliminary data suggest ALDHi may enhance anti- tumor immunity both via actions on the tumor cell and immune cells. We therefore propose SA3: To determine the ability of ALDHi to enhance immunotherapy in OvCa. To test this hypothesis, we will use several immune competent models of OvCa to determine the ability of ALDHi to enhance checkpoint inhibitor therapy and antitumor vaccines. IMPACT: While immune therapy has demonstrated significant benefit in many cancers, the impact in OvCa has been limited. The studies proposed here will define the role for a novel therapeutic ALDHi in immunotherapy in OvCa. Given ALDH is broadly linked with therapeutic resistance in cancer, these studies will have far-reaching implications for cancer therapy.

卵巢癌（OVCA）是一种致命疾病，在女性中癌症死亡中排名第五，死亡率最高第三 所有癌症的发病率比。几十年来，患者的总体生存期没有显着改变，那里 对于开发OVCA的新疗法是明显的未满足的临床需求。醛脱氢酶1a酶 （ALDH1A）代表OVCA的治疗靶标。 Aldh1a酶在卵巢癌中上调 引发细胞（CIC）并介导视黄酸（RA）的生物合成，以调节众多细胞 过程。我们最近确定了一种新型的ALDH1A家族抑制剂（ALDHI）。我们的初步数据表示 Aldhi治疗癌细胞和免疫细胞具有相反的作用，这两者都可以促进抗 肿瘤免疫。 CIC的Aldhi治疗诱导RA和转录依赖性坏死细胞死亡， 可能与RA转录伙伴NR4A1的功能改变有关。这种Aldhi引起的CIC死亡是 与损害相关的分子模式（湿）和其他炎症的释放相关 调解人。相反，Aldhi处理与两个树突状细胞的增殖反应增强有关 （DC）和CD8+ T细胞。我们的总体假设是Aldhi可以充当免疫调节剂，并且 可用于增强OVCA的免疫治疗方法。为了检验我们的假设，我们提出了 以下特定目的：SA1：确定驱动Aldhi诱导CIC的RA受体和下游因素 坏死并确定Aldhi诱导的CIC坏死性是否是炎症细胞死亡。我们建议 测试单个RA受体RAR/RXR和NR4A1共受体在Aldhi介导的CIC死亡和 评估Aldhi/NR4A1对CIC释放炎症介质的影响，并刺激抗 肿瘤T细胞反应。接下来，我们将在SA2中：评估Aldhi对主机DC和T的影响 细胞。由于RA可以调节T细胞和DC的分化，因此我们将使用报告基因小鼠评估角色 Aldhi在体外和体内破坏RA/NR4A1信号传导以及DC和T细胞生物学。我们将评估 DC分化为产生DC1的IL-12的能力，而CD4 T辅助细胞子集与 专注于TH17/Treg trans分差。最后，我们的初步数据表明Aldhi可能会增强反抗 肿瘤免疫都通过对肿瘤细胞和免疫细胞的作用。因此，我们建议SA3：确定 Aldhi增强OVCA免疫疗法的能力。为了检验这一假设，我们将使用几种免疫 OVCA的合格模型来确定Aldhi增强检查点抑制剂疗法的能力和 抗肿瘤疫苗。 影响：虽然免疫治疗在许多癌症中都显示出显着的好处，但OVCA的影响 受到限制。这里提出的研究将定义新的治疗性ALDHI在免疫疗法中的作用 OVCA。鉴于ALDH与癌症的治疗性抗性广泛联系在一起，这些研究将具有深远的影响 对癌症治疗的影响。