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:
- 金额:$ 44.15万
- 依托单位:
- 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:
- 关键词:Antigen-Presenting CellsAntigensBiological AssayCD8B1 geneCause of DeathCellsClinicalCombined Modality TherapyComplexCross-PrimingCytotoxic T-LymphocytesDNADNA DamageDiagnosisElectronsEnzymesGenomicsGoalsImmuneImmune checkpoint inhibitorImmunotherapyIndividualInterferon Type IInterferonsMacrophageMalignant NeoplasmsMediatingMitochondriaMitochondrial DNAModelingMolecularMusNatural ImmunityNecrosisNeutrophil InfiltrationOxidoreductasePD-1 blockadePatternPhagocytesPharmaceutical PreparationsProdrugsProductionQuinonesReactive Oxygen SpeciesRefractoryRelapseResearchResistanceRoleSignal TransductionSolidSolid NeoplasmSourceStimulator of Interferon GenesT-LymphocyteTherapeuticTumor ImmunityTumor SuppressionUp-Regulationadaptive immunityanti-PD-L1anti-PD-L1 therapyanti-tumor immune responsebeta-Lapachonecancer cellimmune checkpoint blockadeimmunogenic cell deathimprovedin vivoinnate immune sensingneoplastic cellneutrophilnew combination therapiesnovelpre-clinicalprogrammed cell death ligand 1recruitresistance mechanismresponsesynergismtargeted treatmenttherapeutic vaccinetumortumor DNAtumor growthtumor microenvironmentuptake
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:
- 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:
- 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.
- DOI:10.3389/fonc.2022.975981
- 发表时间:2022
- 期刊:
- 影响因子:4.7
- 作者:
- 通讯作者:
KP372-1-Induced AKT Hyperactivation Blocks DNA Repair to Synergize With PARP Inhibitor Rucaparib via Inhibiting FOXO3a/GADD45α Pathway.
- DOI:10.3389/fonc.2022.976292
- 发表时间:2022
- 期刊:
- 影响因子:4.7
- 作者:
- 通讯作者:
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{{ truncateString('Xiumei Huang', 18)}}的其他基金
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
- 批准号:
10428620 - 财政年份:2020
- 资助金额:
$ 44.15万 - 项目类别:
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
- 批准号:
10215446 - 财政年份:2020
- 资助金额:
$ 44.15万 - 项目类别:
Tumor-selective radiosensitization of NSCLC using NQO1 bioactivatable drugs
使用 NQO1 生物可激活药物对 NSCLC 进行肿瘤选择性放射增敏
- 批准号:
10322435 - 财政年份:2018
- 资助金额:
$ 44.15万 - 项目类别:
Tumor-selective use of PARP inhibitors against NQO1+ nonsmall cell lung cancer
PARP 抑制剂针对 NQO1 非小细胞肺癌的肿瘤选择性使用
- 批准号:
10054962 - 财政年份:2017
- 资助金额:
$ 44.15万 - 项目类别:
Tumor-selective use of PARP inhibitors against NQO1+ nonsmall cell lung cancer
PARP 抑制剂针对 NQO1 非小细胞肺癌的肿瘤选择性使用
- 批准号:
10304927 - 财政年份:2017
- 资助金额:
$ 44.15万 - 项目类别:
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