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) 是一种致命疾病，在女性癌症死亡中排名第五，死亡率排名第三与所有癌症的发病率之比。由于患者的总生存率几十年来没有显着变化，开发 OvCa 新疗法是一个明显未满足的临床需求。醛脱氢酶-1A酶 (ALDH1A) 代表 OvCa 的治疗靶点。卵巢癌中 ALDH1A 酶上调起始细胞 (CIC) 并介导视黄酸 (RA) 的生物合成，调节众多细胞流程。我们最近发现了一种新型 ALDH1A 家族抑制剂 (ALDHi)。我们的初步数据表明 ALDHi 治疗癌细胞和免疫细胞具有相反的作用，两者都可以促进抗- 肿瘤免疫。 CIC 的 ALDHi 治疗诱导 RA 和转录依赖性坏死性细胞死亡，可能与 RA 转录伴侣 NR4A1 的功能改变有关。这种 ALDHi 诱导的 CIC 死亡是与损伤相关分子模式 (DAMP) 和其他炎症的释放有关调解员。相比之下，ALDHi 治疗与树突状细胞的增殖反应增强相关 (DC) 和 CD8+ T 细胞。我们的首要假设是 ALDHi 可以充当免疫调节剂可用于增强 OvCa 的免疫治疗方法。为了检验我们的假设，我们提出以下具体目标： SA1：识别 RA 受体和驱动 ALDHi 诱导的 CIC 的下游因素坏死并确定 ALDHi 诱导的 CIC 坏死性凋亡是否是炎症细胞死亡。我们建议测试单个 RA 受体 RAR/RXR 和 NR4A1 辅助受体在 ALDHi 介导的 CIC 死亡中的作用，以及评估 ALDHi/NR4A1 对 CIC 炎症介质释放的影响以及抗- 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，我们将使用报告小鼠来评估其作用 ALDHi 对 RA/NR4A1 信号传导以及体外和体内 DC 和 T 细胞生物学破坏的影响。我们将评估 DC 分化为产生 IL-12 的 DC1 和 CD4 T 辅助细胞亚群分化的能力重点关注 Th17/Treg 转分化。最后，我们的初步数据表明 ALDHi 可能会增强抗- 肿瘤免疫通过对肿瘤细胞和免疫细胞的作用。因此我们提出 SA3：确定 ALDHi 增强 OvCa 免疫治疗的能力。为了检验这个假设，我们将使用几种免疫 OvCa 的能力模型可以确定 ALDHi 增强检查点抑制剂治疗的能力抗肿瘤疫苗。影响：虽然免疫疗法已证明对许多癌症具有显着益处，但对 OvCa 的影响受到限制。这里提出的研究将定义新型治疗 ALDHi 在免疫治疗中的作用奥夫卡。鉴于 ALDH 与癌症的治疗耐药性广泛相关，这些研究将产生深远的影响对癌症治疗的影响。