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.

抽象的我们的长期目标是开发新型的抗肿瘤疗法，以升高（> 100倍）的癌症治疗癌症 NAD（P）H：喹酮氧化还原酶1（NQO1）。 NQO1生物活化药物，有选择性地靶向NQO1+肿瘤，并被NQO1激活以产生活性氧（ROS），导致广泛的DNA损伤和PARP1驱动的肿瘤编程坏死。我们的初步研究表明抗肿瘤需要中性粒细胞介导的先天免疫和CD8介导的适应性免疫 β-大束在体内的功效。此外，我们以前的研究表明，针对NQO1潜在的靶向可能会触发先天性在肿瘤微环境（TME）内感测，可以通过免疫疗法协同克服适应性反抗。我们的目的是定义和描述肿瘤特异性ROS和DNA的机制由β-宽带造成的损害，β-宽带刺激了抗弱者免疫，并确定β-宽度如何与免疫协同作用检查点封锁治疗。我们的中心假设是（i）β-束治疗触发免疫原性死亡（ICD）并诱导与损伤相关的分子模式（潮湿）释放；（ii）吞噬细胞/抗原呈递募集的细胞（APC）促进细胞毒性T细胞（CTL）的交叉染色，以抑制肿瘤增加抗原/DNA摄取和I型干扰素（IFNS）生产；（iii）在TME内上调PD-L1 有助于肿瘤的释放，并为β-宽合并和免疫的结合治疗提供治疗窗口检查点封锁。我们提出以下特定目标。 AIM 1：阐明β-拉普 - 的机制触发了ICD先天免疫感应。我们的工作假设是β-大束触发了ICD用于先天感应的ICD 通过潮湿的释放。我们将评估通过治疗疫苗在体内刺激肿瘤ICD的能力测定。我们还将确定哪种类型的肿瘤DNA（基因组或线粒体）是主要来源 β-大束治疗后的IFN产生。 AIM 2：定义肿瘤细胞和免疫细胞如何串扰在β-lap诱导的抗毒液免疫中。我们的工作假设是β-宽诱导的中性粒细胞交叉prime T 细胞直接或与DC/巨噬细胞相互作用，与质子T细胞相互作用。我们将确定β-束处理的影响在CGA/sting/IFN上参与T细胞交叉染色。 AIM 3：确定β-盖的机制与免疫检查点阻断疗法协同作用，有效地杀死NQO1+肿瘤。我们的工作假设是，TME内的PD-L1增加在初始反应后导致大肿瘤的肿瘤缓解到β-盖。我们将确定在TME中更新的细胞PD-L1表达类型。我们也会确定哪种表达PD-L1的细胞的类型对于与条件的小鼠的协同作用至关重要肿瘤，DC或巨噬细胞上PD-L1的缺陷。影响：这些研究将描述β-束的作用在导致T细胞依赖性肿瘤控制的肿瘤选择性感应中。此外，我们将阐明如何β- 克服对抗PD-L1治疗的自适应耐药性。这项研究将为新的新证据提供新的证据 NQO1+实体瘤的组合疗法，并扩大免疫检查点抑制剂的临床实用性。

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.