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ALDH Inhibition as Modulator of Tumor Immunobiology

ALDH 抑制作为肿瘤免疫生物学的调节剂

基本信息

批准号：
10649413
负责人：
Ronald J Buckanovich
金额：
$ 42.77万
依托单位：
MAGEE-WOMEN'S RES INST AND FOUNDATION
依托单位国家：
美国
项目类别：
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/10649413
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 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 MUC1 gene Malignant Neoplasms Malignant neoplasm of ovary Mediating Modeling Molecular Mucin 1 protein Mus NR4A1 gene Necrosis Nuclear Receptors Patients Pattern Phenotype Production Proliferating RXR Regulatory T-Lymphocyte Reporter Resistance Retinoic Acid Receptor Role Signal Transduction T cell differentiation T cell infiltration T cell response T-Cell Activation T-Lymphocyte Testing Therapeutic Transgenic Mice Tretinoin Tumor Antigens Tumor Immunity Tumor-Infiltrating Lymphocytes Up-Regulation Vaccines Woman aldehyde dehydrogenases cancer cell cancer immunotherapy cancer initiation cancer therapy carcinogenesis 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 pharmacologic receptor response stemness therapeutic target therapy resistant transcription factor transcriptome sequencing transdifferentiation tumor

项目摘要

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）是一种致命的疾病，在女性癌症死亡中排名第五，死亡率排名第三所有癌症的发病率。由于患者的总体生存期在几十年内没有显著变化，是开发OvCa新疗法的明显未满足的临床需求。醛脱氢酶-1A （ALDH 1A）代表OvCa的治疗靶标。卵巢癌中ALDH 1A酶上调启动细胞（CIC），并介导视黄酸（RA）的生物合成，以调节许多细胞流程.我们最近发现了一种新的ALDH 1A家族抑制剂（ALDHi）。我们的初步数据显示 ALDHi治疗癌细胞和免疫细胞有相反的效果，两者都可以促进抗- 肿瘤免疫CIC的ALDHi处理诱导RA和转录依赖性坏死性细胞死亡，可能与RA转录伴侣NR 4A 1的功能改变有关。这种ALDHi诱导的CIC死亡是与释放损伤相关分子模式（DAMP）和其他炎性调解员相比之下，ALDHi治疗与两种树突状细胞的增殖反应增强相关。 (DC)CD 8 + T细胞。我们的首要假设是ALDHi可以作为免疫调节剂，可用于增强OvCa中的免疫抑制方法。为了验证我们的假设，我们提出了 SA 1：鉴定驱动ALDHi诱导的CIC的RA受体和下游因子以确定ALDHi诱导的CIC坏死性凋亡是否为炎性细胞死亡。我们建议测试单个RA受体RAR/RXR和NR 4A 1共受体在ALDHi介导的CIC死亡中的作用，评估ALDHi/NR 4A 1对炎症介质的CIC释放的影响，以及这种抗炎症介质的刺激。肿瘤T细胞反应。接下来，我们将在SA 2中：评估ALDHi对宿主DC和T的影响细胞由于RA可以调节T细胞和DC的分化，我们将使用报告小鼠来评估RA的作用 ALDHi对RA/NR 4A 1信号传导以及DC和T细胞生物学的破坏。我们将评估 DC分化为产生IL-12的DC 1的能力，以及CD 4辅助性T细胞亚群的分化 Th 17/Treg转分化。最后，我们的初步数据表明，ALDHi可以增强抗- 肿瘤免疫通过作用于肿瘤细胞和免疫细胞。因此，我们建议SA 3： ALDHi增强OvCa中免疫治疗的能力。为了验证这一假设，我们将使用几种免疫 OvCa的胜任模型以确定ALDHi增强检查点抑制剂治疗的能力，抗肿瘤疫苗影响：虽然免疫治疗在许多癌症中表现出显着的益处，但OvCa的影响被限制。本文提出的研究将定义新型治疗性ALDHi在免疫治疗中的作用， OvCa。鉴于ALDH与癌症的治疗耐药性广泛相关，这些研究将具有深远的意义。对癌症治疗的影响