Immunomodulatory effects of bortezomib on antitumor CD8 T-NK cell crosstalk
硼替佐米对抗肿瘤 CD8 T-NK 细胞串扰的免疫调节作用
基本信息
- 批准号:9770536
- 负责人:
- 金额:$ 32.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-07-12 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdoptive Cell TransfersAdoptive ImmunotherapyAdoptive TransferAffectAlpha CellAntigensApoptosisAvidityBortezomibCD8-Positive T-LymphocytesCD8B1 geneCancer ModelCell TherapyChronicClinicClinicalCytolysisDataDendritic CellsDevelopmentDisease remissionDoseEffector CellEpidermal Growth Factor ReceptorEpitopesExhibitsExtramural ActivitiesFunctional disorderFundingGoalsHemagglutininHematopoieticImageImmuneImmune checkpoint inhibitorImmune responseImmunosuppressionImmunosuppressive AgentsInflammationInflammatoryInterleukin 2 ReceptorInvestigationKnockout MiceLigandsLung AdenocarcinomaLymphocyteMalignant NeoplasmsMalignant neoplasm of lungMediatingModelingMolecularMusMutationNatural Killer CellsPhosphorylationProteasome InhibitorRefractoryRegimenRelapseResistanceRoleSignal PathwaySignal TransductionSignaling MoleculeSolid NeoplasmSurvival RateSystemT-Cell ReceptorT-Lymphocyte and Natural Killer CellTestingTherapeuticTissuesTraining ProgramsTranslationsTumor DebulkingTumor EscapeTumor ImmunityVariantbasecancer cellcancer immunotherapycell typeclinically relevantcombinatorialgenetic approachimmunoregulationimproved functioninginnovationinsightintravital imaginglymph nodeslymphocyte proliferationmelanomamutantneoplastic cellnotch proteinnovelnovel strategiesp65pre-clinicalpreclinical studypreventresponsetargeted treatmenttreatment optimizationtumortumor eradicationtumor growthtumor microenvironment
项目摘要
Adoptive cell immunotherapy with immune checkpoint inhibitors has shown clinical promise. Unfortunately,
despite optimizations of treatments, relapse-free survival rates still range between 17-21% in most metastatic
solid tumors. This occurs via various tumor-induced abnormalities including immunosuppression and
emergence of immune escape tumor variants. Tumor growth can induce immunosuppression by multiple
mechanisms. We identified a novel mechanism of immunosuppression wherein tumor interferes with the host
hematopoietic Notch system that is critical for lymphocyte differentiation and function. Our studies in solid
tumor models demonstrate that lymphocyte teamwork, specifically between CD8+T cell and NK cell effectors, is
essential to eradicate tumor cells. However, immunosuppressive chronic inflammation in the tumor
microenvironment hinders this phenomenon. Thus, strategies that can reverse Notch dysfunction in
lymphocytes and restore the CD8+T–NK crosstalk are critical for effective tumor eradication and durable
remission. Facilitated by SCORE funding support, we found that proteasome inhibitor bortezomib modulates
Notch signaling in lymphocytes and enhances their antitumor activity. Additionally, our data also indicate that
bortezomib may augment CD8+T and NK cell crosstalk. Based on these data, we hypothesize that bortezomib
overcomes tumor-induced immunosuppression by enhancing the antitumor adaptive and innate immune
effector crosstalk via modulation of the hematopoietic Notch system. In this competing renewal application, we
propose to extend our studies to the next level whereby we can advance our basic insights into CD8+T–NK
crosstalk and Notch-mediated lymphocyte mechanisms into a preclinical therapeutic setting. We will test our
hypothesis by addressing how bortezomib can facilitate the CD8+T–NK crosstalk (Aim 1), and Notch-
dependent mechanisms affecting antitumor lymphocyte cross-talk (Aim 2). Investigations will include genetic
approaches based on the use of unique cell type-specific Notch ligand conditional knockout mice that we have
generated to clearly define the roles of dendritic cell-bound ligands in antitumor CD8+T–NK functional
crosstalk. In Aim 3, we propose to evaluate the therapeutic impact of bortezomib-mediated enhancement of
Notch signaling and CD8+T–NK crosstalk on tumor rejection and relapse-free survival. We will use an inducible
lung cancer model carrying EGFR mutations. We will integrate bortezomib and adoptive CD8+T and NK cell
transfers along with EGFR-targeted therapy and evaluate the impact of this combinatorial regimen on tumor
remission and relapse-free survival. Altogether, the studies proposed in this SC1 renewal application will
unravel novel mechanisms underlying lymphocyte antitumor crosstalk, and will provide innovative insight into
modulation of Notch regulatory lymphocyte mechanisms using bortezomib for translation into clinically relevant
therapeutics in advanced-stage, mutant, or resistant lung cancer. In addition, it would enhance the cancer
immunotherapy training program and PI’s capacity to transition to non-SCORE extramural funding support.
使用免疫检查点抑制剂的免疫细胞免疫疗法已显示出临床前景。不幸的是,
尽管优化了治疗,但在大多数转移性肿瘤中,无复发生存率仍在17-21%之间。
实体瘤这是通过各种肿瘤诱导的异常发生的,包括免疫抑制和
免疫逃逸肿瘤变体的出现。肿瘤生长可通过多种途径诱导免疫抑制。
机制等我们发现了一种新的免疫抑制机制,其中肿瘤干扰宿主
造血Notch系统是淋巴细胞分化和功能的关键。我们的研究在固体
肿瘤模型表明,淋巴细胞协同作用,特别是在CD 8 +T细胞和NK细胞效应子之间,
对根除肿瘤细胞至关重要。然而,肿瘤中的免疫抑制性慢性炎症
微环境阻碍了这一现象。因此,可以逆转Notch功能障碍的策略,
淋巴细胞和恢复CD 8 +T-NK串扰对于有效的肿瘤根除和持久的治疗是至关重要的。
缓解。在SCORE基金支持的帮助下,我们发现蛋白酶体抑制剂硼替佐米调节了
Notch在淋巴细胞中的信号传导并增强其抗肿瘤活性。此外,我们的数据还表明,
硼替佐米可增加CD 8 +T和NK细胞的相互作用。基于这些数据,我们假设硼替佐米
通过增强抗肿瘤适应性免疫和先天免疫来克服肿瘤诱导的免疫抑制
通过调节造血Notch系统的效应子串扰。在这个竞争性的续期申请中,我们
我建议将我们的研究扩展到一个新的水平,从而我们可以推进我们对CD 8 +T-NK的基本见解
串扰和Notch介导的淋巴细胞机制应用于临床前治疗环境。我们将测试
通过解决硼替佐米如何促进CD 8 +T-NK串扰的假设(目的1),以及Notch-
影响抗肿瘤淋巴细胞串扰的依赖性机制(目的2)。调查将包括遗传
基于使用独特的细胞类型特异性Notch配体条件性敲除小鼠的方法,
产生了明确定义树突状细胞结合的配体在抗肿瘤CD 8 +T-NK功能中的作用,
串话。在目标3中,我们建议评估硼替佐米介导的增强肿瘤细胞增殖的治疗作用。
Notch信号传导和CD 8 +T-NK串扰对肿瘤排斥和无复发生存的影响我们会用诱导剂
携带EGFR突变的肺癌模型。我们将整合硼替佐米和过继性CD 8 +T和NK细胞,
转移沿着EGFR靶向治疗,并评估这种组合方案对肿瘤的影响
缓解和无复发生存期。总而言之,本次SC 1更新申请中提出的研究将
解开淋巴细胞抗肿瘤串扰的新机制,并将提供创新的见解,
使用硼替佐米调节Notch调节性淋巴细胞机制,用于翻译成临床相关的
晚期、突变型或耐药型肺癌的治疗。此外,它还会增强癌症
免疫治疗培训计划和PI过渡到非SCORE校外资助支持的能力。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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Anil Shanker其他文献
Anil Shanker的其他文献
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{{ truncateString('Anil Shanker', 18)}}的其他基金
Diversity Center for Genome Research at Meharry
梅哈里基因组研究多样性中心
- 批准号:
10749781 - 财政年份:2023
- 资助金额:
$ 32.74万 - 项目类别:
Defining the effects of bortezomib on NK cell activation in cancer
确定硼替佐米对癌症 NK 细胞活化的影响
- 批准号:
8475316 - 财政年份:2013
- 资助金额:
$ 32.74万 - 项目类别:
Defining the effects of bortezomib on NK cell activation in cancer
确定硼替佐米对癌症 NK 细胞活化的影响
- 批准号:
9088384 - 财政年份:2013
- 资助金额:
$ 32.74万 - 项目类别:
Defining the effects of bortezomib on NK cell activation in cancer
确定硼替佐米对癌症 NK 细胞活化的影响
- 批准号:
8700356 - 财政年份:2013
- 资助金额:
$ 32.74万 - 项目类别:
Pilot Project Developing immune checkpoint controlled -release biomaterials for cancer immunology
开发用于癌症免疫学的免疫检查点控释生物材料试点项目
- 批准号:
10493428 - 财政年份:2011
- 资助金额:
$ 32.74万 - 项目类别:
Pilot Project Developing immune checkpoint controlled -release biomaterials for cancer immunology
开发用于癌症免疫学的免疫检查点控释生物材料试点项目
- 批准号:
10327935 - 财政年份:2011
- 资助金额:
$ 32.74万 - 项目类别:
Defining immune footprint in tumor microenvironment following high salt synergized inflammatory cytokine mediated breast cancer progression
定义高盐协同炎症细胞因子介导的乳腺癌进展后肿瘤微环境中的免疫足迹
- 批准号:
10012769 - 财政年份:2011
- 资助金额:
$ 32.74万 - 项目类别:
Pilot Project Developing immune checkpoint controlled -release biomaterials for cancer immunology
开发用于癌症免疫学的免疫检查点控释生物材料试点项目
- 批准号:
10705096 - 财政年份:2011
- 资助金额:
$ 32.74万 - 项目类别:
Defining immune footprint in tumor microenvironment following high salt synergized inflammatory cytokine mediated breast cancer progression
定义高盐协同炎症细胞因子介导的乳腺癌进展后肿瘤微环境中的免疫足迹
- 批准号:
9211644 - 财政年份:
- 资助金额:
$ 32.74万 - 项目类别:
Defining immune footprint in tumor microenvironment following high salt synergized inflammatory cytokine mediated breast cancer progression
定义高盐协同炎症细胞因子介导的乳腺癌进展后肿瘤微环境中的免疫足迹
- 批准号:
9765058 - 财政年份:
- 资助金额:
$ 32.74万 - 项目类别:














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