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Targeting NQO1+ tumor to trigger innate and adaptive immunity

靶向 NQO1 肿瘤以触发先天性和适应性免疫

基本信息

批准号：
10654624
负责人：
Xiumei Huang
金额：
$ 44.15万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2020-07-13 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654624
关键词：
Antigen-Presenting Cells Antigens Biological Assay CD8B1 gene Cause of Death Cells Clinical Combined Modality Therapy Complex Cross-Priming Cytotoxic T-Lymphocytes DNA DNA Damage Diagnosis Electrons Enzymes Genomics Goals Immune Immune checkpoint inhibitor Immunotherapy Individual Interferon Type I Interferons Macrophage Malignant Neoplasms Mediating Mitochondria Mitochondrial DNA Modeling Molecular Mus Natural Immunity Necrosis Neutrophil Infiltration Oxidoreductase PD-1 blockade Pattern Phagocytes Pharmaceutical Preparations Prodrugs Production Quinones Reactive Oxygen Species Refractory Relapse Research Resistance Role Signal Transduction Solid Solid Neoplasm Source Stimulator of Interferon Genes T-Lymphocyte Therapeutic Tumor Immunity Tumor Suppression Up-Regulation adaptive immunity anti-PD-L1 anti-PD-L1 therapy anti-tumor immune response beta-Lapachone cancer cell immune checkpoint blockade immunogenic cell death improved in vivo innate immune sensing neoplastic cell neutrophil new combination therapies novel pre-clinical programmed cell death ligand 1 recruit resistance mechanism response synergism targeted treatment therapeutic vaccine tumor tumor DNA tumor growth tumor microenvironment uptake

项目摘要

ABSTRACT Our long-term goal is to develop novel antitumor therapies to treat cancer with elevated (> 100-fold) levels of NAD(P)H:quinone oxidoreductase 1 (NQO1). β-Lapachone (β-lap), an NQO1 bioactivatable drug, selectively targets NQO1+ tumors and is activated by NQO1 to generate reactive oxygen species (ROS), leading to extensive DNA damage and PARP1-driven tumor programmed necrosis. Our preliminary studies demonstrate that both neutrophil-mediated innate immunity and CD8-mediated adaptive immunity are required for antitumor efficacy of β-lap in vivo. Furthermore, our previous studies reveal that targeting NQO1 potently triggers innate sensing within tumor microenvironment (TME) that synergizes with immunotherapy to overcome adaptive resistance. Our objective here is to define and delineate the mechanism(s) of tumor-specific ROS and DNA damage induced by β-lap that stimulates antitumor immunity, and determine how β-lap synergizes with immune checkpoint blockade therapy. Our central hypothesis is that (i) β-lap treatment triggers immunogenic cell death (ICD) and induces damage-associated molecular patterns (DAMPs) release;; (ii) phagocytes/antigen-presenting cells (APCs) recruitment promotes cross-priming of cytotoxic T cells (CTLs) for suppression of tumor by increasing antigen/DNA uptake and type I interferons (IFNs) production;; and (iii) upregulated PD-L1 within TME contributes to tumor relapse and provides therapeutic window for combination therapy of β-lap with immune checkpoint blockade. We propose the following Specific Aims. AIM 1: Elucidate the mechanism of β-lap- triggered ICD for innate immune sensing. Our working hypothesis is that β-lap triggers ICD for innate sensing via the release of DAMPs. We will assess the ability of β-lap to stimulate tumor ICD in vivo by therapeutic vaccine assay. We will also determine which type(s) of tumor DNA (genomic or mitochondrial) is the major source(s) of IFNs production after β-lap treatment. AIM 2: Define how tumor cells and immune cells cross-talk occurs in β-lap-induced antitumor immunity. Our working hypothesis is that β-lap-induced neutrophils cross-prime T cells directly or interact with DCs/macrophages to prime T cells. We will determine the effects of β-lap treatment on cGAS/STING/IFNs involved in T cells cross-priming. AIM 3: Determine the mechanism by which β-lap synergizes with immune checkpoint blockade therapy to efficaciously kill NQO1+ tumors. Our working hypothesis is that increased PD-L1 within TME contributes to tumor relapse of large tumors after initial responses to β-lap. We will determine in which type(s) of cells PD-L1 expression is upregulated within TME. We will also determine which type(s) of PD-L1-expressing cells is essential for the synergistic effect in mice with conditional deficiencies of PD-L1 on tumors, DCs or macrophages. IMPACT: These studies will delineate the role of β-lap in tumor-selective innate sensing that leads to T cell-dependent tumor control. Further, we will elucidate how β- lap overcomes adaptive resistance to anti-PD-L1 therapy. This research will provide novel evidence for new combination therapy for NQO1+ solid tumors and broaden the clinical utility of immune checkpoint inhibitors.

摘要我们的长期目标是开发新的抗肿瘤疗法，以治疗高水平（> 100倍）的癌症。 NAD（P）H：醌氧化还原酶1（NQO1）。β-异拉帕酮（β-Lapaclap），一种NQO1生物活化药物，选择性地靶向NQO1+肿瘤，并被NQO1激活产生活性氧（ROS），导致广泛的DNA损伤和PARP1-β驱动的肿瘤程序性坏死。我们的初步研究表明中性粒细胞介导的先天免疫和CD8-T介导的适应性免疫都是抗肿瘤免疫所必需的。此外，我们以前的研究表明，靶向NQO1有效地触发了先天性的肿瘤微环境（TME）内的传感与免疫疗法协同作用，以克服适应性我们的目的是确定和描述肿瘤特异性ROS和DNA的作用机制。 β-Alkylap诱导的损伤，刺激抗肿瘤免疫，并确定β-Alkylap如何协同免疫我们的中心假设是（i）β-glap治疗触发免疫原性细胞死亡， (ICD)并诱导损伤相关分子模式（DAMPs）的释放;（ii）吞噬细胞/抗原呈递细胞（APCs）募集促进细胞毒性T细胞（CTL）的交叉免疫启动，增加抗原/DNA摄取和I型干扰素（IFN）产生;（iii）TME内PD-IL1上调有助于肿瘤复发，并为β-肾上腺素联合免疫治疗提供了治疗窗口目的1：阐明β-淀粉样蛋白lap-β的作用机制我们的工作假设是β-glap触发先天免疫感应的ICD 通过释放DAMPs，我们将评估β-glap通过治疗性疫苗在体内刺激肿瘤ICD的能力。我们还将确定哪种类型的肿瘤DNA（基因组或线粒体）是肿瘤DNA的主要来源。目的2：明确肿瘤细胞和免疫细胞如何发生交叉干扰我们的工作假设是，β-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap-glap 细胞直接或与DC/巨噬细胞相互作用以引发T细胞。我们将确定β-DCs治疗的效果目的3：确定β-IFN-γ与cGAS/STING/IFN-γ相互作用的机制。与免疫检查点阻断疗法协同作用，有效杀死NQO 1+肿瘤。假设TME内PD-IL1增加有助于大肿瘤在初始应答后的肿瘤复发我们将确定在TME内哪种类型的细胞中PD-IL1表达上调。确定哪种类型的PD-IL1-IL1表达细胞对于条件性免疫缺陷小鼠中的协同效应是必需的。影响：这些研究将描述β-PDL1在肿瘤、DC或巨噬细胞上的作用。在肿瘤细胞选择性的先天感应中，β-环糊精导致T细胞依赖性的肿瘤控制。 lap克服了对抗PD-IL1治疗的适应性耐药性。这项研究将为新的本发明提供了用于NQO1+实体瘤的联合疗法，并拓宽了免疫检查点抑制剂的临床效用。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

β-Lapachone Selectively Kills Hepatocellular Carcinoma Cells by Targeting NQO1 to Induce Extensive DNA Damage and PARP1 Hyperactivation.

DOI：
10.3389/fonc.2021.747282
发表时间：
2021
期刊：
Frontiers in oncology
影响因子：
4.7
作者：
Zhao W;Jiang L;Fang T;Fang F;Liu Y;Zhao Y;You Y;Zhou H;Su X;Wang J;Liu S;Chen Y;Wan J;Huang X
通讯作者：
Huang X

Augmented Concentration of Isopentyl-Deoxynyboquinone in Tumors Selectively Kills NAD(P)H Quinone Oxidoreductase 1-Positive Cancer Cells through Programmed Necrotic and Apoptotic Mechanisms.

DOI：
10.3390/cancers15245844
发表时间：
2023-12-14
期刊：
CANCERS
影响因子：
5.2
作者：
Wang, Jiangwei;Su, Xiaolin;Jiang, Lingxiang;Boudreau, Matthew W.;Chatkewitz, Lindsay E.;Kilgore, Jessica A.;Zahid, Kashif Rafiq;Williams, Noelle S.;Chen, Yaomin;Liu, Shaohui;Hergenrother, Paul J.;Huang, Xiumei
通讯作者：
Huang, Xiumei

Neutrophils: Musketeers against immunotherapy.