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: 10380368
• 负责人: Ronald J Buckanovich
• 金额: $ 6.04万
• 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/10380368
• 关键词: Anabolism; Blood; Bone Marrow; CD8-Positive T-Lymphocytes; Cell Death; Cell physiology; Cells; Cessation of life; Clinical; Dendritic Cells; Disease; Enzyme Inhibitor Drugs; Enzymes; Frequencies; Goals; Health; Human; Immune; Immunobiology; Immunomodulators; Immunotherapeutic agent; Immunotherapy; Incidence; Individual; Inflammatory; Knockout Mice; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mission; Mus; NR4A1 gene; Necrosis; Patients; Protocols documentation; RXR; Reporter; Research; Research Personnel; Retinoic Acid Receptor; Role; Science; Signal Transduction; Specificity; T-Lymphocyte; Testing; Tretinoin; Tumor-associated macrophages; United States National Institutes of Health; Woman; Work; aldehyde dehydrogenases; cancer therapy; in vivo; macrophage; mortality; neoplasm immunotherapy; neoplastic cell; novel therapeutics; ovarian neoplasm; parent grant; receptor; response; standard of care; therapeutic target; therapy resistant; tumor; tumor microenvironment

Despite small improvements to standard of care protocols, the overall survival of patients with ovarian cancer (OvCa) has not significantly changed for several decades. There is a clear unmet clinical need to develop new therapies for this highly aggressive disease ranking 5th in cancer deaths in women, with the 3rd highest mortality to incidence ratio of all cancers. Aldehyde dehydrogenase-1A enzymes (ALDH1A) represent a therapeutic target for OvCa. ALDH1A enzymes are upregulated in ovarian cancer initiating cells where they mediate the biosynthesis of retinoic acid (RA), to regulate numerous cellular processes. We recently demonstrated that inhibition of ALDH1A (ALDHi) can have a dual effect: it can directly target tumor cells to slow proliferation and act on immune cells to enhance proliferative response of both dendritic cells (DC) and CD8+ T cells. Our overarching hypothesis is that ALDHi can act as an immune modulator (via individual RA receptors RAR/RXR and NR4A1 co-receptor) and can be used to enhance immunotherapeutic approaches in OvCa. To test this hypothesis, our five-year project R01CA238315, the parent grant to this Research Supplement to Promote Diversity in Health-Related Research, proposes three specific aims (SA) SA1: To identify the RA receptors and downstream factors that drive ALDHi induced necrosis in tumor cells and to determine whether ALDHi-induced CIC necroptosis is inflammatory cell death. SA2: Assess the impact of ALDHi on host DC and T cells. SA3: To determine the ability of ALDHi to enhance immunotherapy in OvCa. The current, one-year project builds on our new findings showing that, in addition to their immune promoting function in DCs and CD8 T cells, ALDHi also lower the frequency of tumor associated macrophages (TAM), a critically important immune cell subset with immune suppressive, tumor-promoting function. The goal of the current one-year proposal is to extend our studies (originally focused on DC and T cells) to (1) identify the mechanisms of ALDHi induced effects on TAM and (2) elucidate the downstream consequences of these ALDHi effects on modulating the tumor microenvironment and enhancing immune therapy response. To achieve this, we will use primary macrophages derived ex vivo from blood (human) or bone marrow precursors (mice) and matured under M1/M2 inducing conditions in the presence or absence of ALDHi. NR4A1 involvement will be dissected using bone marrow precursors from NR4A1 reporter mice and target specificity will be confirmed in NR4A1 null mice. The immune modulatory roles of TAM will be further dissected in vivo, in NR4A1 mice challenged orthotopically with ovarian tumors and treated with ALDHi or vehicle control. IMPACT: This project is in line with the NIH mission to promote diversity among investigators doing research in health-related sciences. The studies proposed here will define new roles for a ALDHi in immunotherapy in OvCa. Given ALDH is broadly linked with therapeutic resistance in cancer, our work will have far-reaching implications for cancer therapy.

尽管标准治疗方案略有改善，但卵巢癌患者的总生存率 （OvCa）几十年来没有发生重大变化。有一个明确的未满足的临床需求，以开发新的 这种高度侵袭性疾病的治疗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。乙醛脱氢酶-1A酶（ALDH 1A）代表治疗靶点 关于OvCa ALDH 1A酶在卵巢癌起始细胞中上调，它们介导卵巢癌的发生。 视黄酸（RA）的生物合成，以调节许多细胞过程。我们最近证明， ALDH 1A（ALDHi）的抑制可以具有双重作用：它可以直接靶向肿瘤细胞以减缓增殖， 作用于免疫细胞以增强树突状细胞（DC）和CD 8 + T细胞的增殖应答。我们 总体假设是ALDHi可以作为免疫调节剂（通过单个RA受体 RAR/RXR和NR 4A 1共受体），并可用于增强OvCa中的免疫抑制方法。 为了验证这一假设，我们的五年期项目R 01 CA 238315，对本研究补充的母基金， 促进健康相关研究的多样性，提出了三个具体目标（SA）SA 1：确定RA 受体和下游因子驱动ALDHi诱导肿瘤细胞坏死，并确定是否 ALDHi诱导的CIC坏死性凋亡是炎性细胞死亡。SA 2：评估ALDHi对宿主DC和T细胞的影响 细胞SA 3：确定ALDHi增强OvCa中的免疫疗法的能力。目前为期一年的项目 基于我们的新发现，除了它们在DC和CD 8 T细胞中的免疫促进功能外， ALDHi还降低了肿瘤相关巨噬细胞（TAM）的频率，TAM是一种非常重要的免疫细胞， 具有免疫抑制、肿瘤促进功能亚群。目前一年期提案的目标是 将我们的研究（最初集中在DC和T细胞）扩展到（1）确定ALDHi诱导效应的机制 和（2）阐明这些ALDHi调节肿瘤的作用的下游后果 微环境和增强免疫治疗反应。为了实现这一目标，我们将使用原代巨噬细胞 从血液（人）或骨髓前体（小鼠）离体衍生并在M1/M2诱导下成熟 在存在或不存在ALDHi的条件下。将使用骨髓解剖NR 4A 1受累 将在NR 4A 1缺失小鼠中证实来自NR 4A 1报告小鼠的前体和靶特异性。免疫 TAM的调节作用将在体内进一步分析，在用卵巢癌原位激发的NR 4A 1小鼠中， 肿瘤并用ALDHi或载体对照处理。 影响：该项目符合NIH的使命，即促进从事研究的研究人员的多样性 与健康有关的科学。本文提出的研究将定义ALDHi在OvCa免疫治疗中的新作用。 鉴于ALDH与癌症的治疗耐药性广泛相关，我们的工作将产生深远的影响 用于癌症治疗。