权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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一种新型的抗肿瘤药物，以更好地治疗癌症，并将药物水平提高100倍。 NAD(P)H：苯二酚氧化还原酶1(NQO1)。β-拉帕酮(β-LAP)，一种NQO1的生物活性药物，选择性地。靶向NQO1+的肿瘤细胞和细胞被NQO1激活，以产生新的活性氧自由基(ROS)，从而导致肿瘤的发生。广泛的DNA损伤和PARP1驱动的肿瘤程序性坏死。我们的初步研究将证明。这既是中性粒细胞介导的天然免疫系统，也是CD8介导的适应性免疫系统抗肿瘤所必需的。 β-LAP在体内的有效性。此外，我们之前的研究表明，靶向NQO1可能会有效地触发先天感染。在肿瘤微环境研究(TME)中感知肿瘤与免疫治疗之间的协同作用，以克服适应性疾病。耐药性。我们在这里的主要目标是定义和描绘肿瘤特异性ROS基因和DNA的作用机制(S)。 β-LAP刺激机体抗肿瘤免疫所造成的损害，决定了β-LAP与免疫系统如何协同作用。检查站封锁治疗。我们的第二个中心假说是，(I)β-lap治疗会触发免疫原性细胞死亡。 (ICD)诱导损伤相关的分子模式(DAMPS)释放；;(II)诱导吞噬细胞/抗原递呈。细胞集落刺激因子(APC)促进细胞毒T细胞亚群(CTL)的交叉激发，从而抑制肿瘤的发生。增加对抗原/DNA的摄取和I型干扰素(;)的产生；I型干扰素和I型干扰素(III)在TME内上调Pd-L1。有助于肿瘤的复发，为β-LAP与免疫系统的联合治疗提供了治疗的窗口。检查站：封锁。我们将提出以下具体目标。目标1：阐明β-LAP--的运行机制。触发了ICD对先天免疫功能的感知。我们最新的工作假说是，β-lap触发了ICD对先天免疫功能的感知。通过药物的释放，我们将继续评估β-lap疫苗通过治疗性疫苗在体内刺激肿瘤和ICD的能力。化验。我们还将确定哪种类型(S)的肿瘤DNA(基因组或线粒体)是癌症的主要来源(S)。 β-LAP治疗后，IFN开始产生。第二个目标：它定义了肿瘤细胞和免疫细胞之间的相互作用是如何发生的。在β-LAP诱导的抗肿瘤免疫中，我们最有效的假说是β-LAP诱导的中性粒细胞与T细胞交叉启动。细胞与DC/巨噬细胞直接接触或相互作用，以激活T细胞。我们将无法确定β-LAP治疗的临床效果。在CGAS/STING/IFN上，参与了T细胞的交叉启动。目标3：确定β-LAP的激活机制。与免疫系统检查站、封锁和治疗系统协同工作，有效地杀死NQO1+肿瘤。我们的工作原理是假说是，在TME治疗中增加的Pd-L1水平有助于在最初的治疗反应后，导致较大肿瘤的肿瘤复发。到β-LAP。我们还不会确定在TME中哪种类型的细胞(S)的PD-L1基因表达上调。我们也将决定。确定哪种类型(S)的PD-L1-表达的细胞对于改善有条件免疫缺陷小鼠的协同效应是至关重要的。 β-L1对肿瘤、树突状细胞或巨噬细胞的作用存在缺陷。其影响：这些研究将进一步勾勒出PPD-L1的重要作用。在肿瘤选择性先天免疫感知机制中，这将导致T细胞依赖的肿瘤免疫控制。此外，我们还将阐明β是如何发挥作用的。 LAP克服了对抗PD-L1治疗的适应性阻力，这一研究成果将为新的治疗提供新的新的证据。联合治疗可用于治疗NQO1+的实体肿瘤，并将拓宽免疫球蛋白检查点抑制剂的临床应用范围。

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.