Melanoma-mediated Dendritic Cell Tolerization and Immune Evasion
黑色素瘤介导的树突状细胞耐受和免疫逃避
基本信息
- 批准号:9310397
- 负责人:
- 金额:$ 16.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-08-04 至 2020-07-31
- 项目状态:已结题
- 来源:
- 关键词:5&apos-AMP-activated protein kinaseAddressAmino AcidsAntigen PresentationAntigen-Presenting CellsAutomobile DrivingCD8-Positive T-LymphocytesCellular Metabolic ProcessChemicalsClinicClinicalClinical TrialsDataDendritic CellsDendritic cell activationDetectionDevelopmentEffectivenessEnzymesEvolutionGene TargetingGenerationsGenetically Engineered MouseGlycolysisHumanImmune EvasionImmune ToleranceImmune checkpoint inhibitorImmune responseImmune systemImmunityImmunologic MonitoringImmunosuppressionImmunotherapeutic agentImmunotherapyIn VitroKynurenineLigandsMalignant NeoplasmsMediatingMetabolicMetabolic PathwayMetabolismMetastatic MelanomaMethodsModelingMolecularPathway interactionsPatientsPharmacologyPhenotypePlayPopulationProcessProgression-Free SurvivalsProtein KinaseRegulatory T-LymphocyteResistanceRoleSentinel Lymph NodeSignal PathwaySignal TransductionSolid NeoplasmT-Cell DevelopmentT-LymphocyteTestingTherapeuticTimeTryptophanTryptophan 2,3 DioxygenaseTumor AntigensTumor BurdenTumor ImmunityTumor-DerivedUp-RegulationWorkbeta catenincancer immunotherapyimmunoregulationin vivoinhibitor/antagonistinsightmelanomaneoplasm immunotherapynew therapeutic targetnoveloncologyoutcome forecastpatient populationpatient subsetsphysiologic modelprogramspublic health relevanceresponsesensortargeted agenttumortumor microenvironmenttumor progression
项目摘要
DESCRIPTION (provided by applicant): While melanoma immunotherapy is starting to show beneficial results in the clinic, only a subset of patients currently benefit from this form of treatment. The development of these cancer immunotherapy approaches has primarily focused on enhancing the function of the T cell while much less work has been devoted to developing strategies to enhance antigen-presenting cell activity. Dendritic cells (DCs) are potent antigen- presenting cells that are capable of both activating tumor antigen-specific T cells and directing their function. It is believed that the limited efficacy of current immunotherapy agents is largely
due to the evolution of methods utilized by developing cancers to avoid detection and destruction by the host immune system. Recent work has shown that cancers are capable of actively tolerizing local DCs, enabling them to promote the expansion of regulatory T cells (Tregs) and maintain a state of immune tolerance. One important component of tumor immune evasion has been determined to be the indoleamine 2,3-dioxygenase (IDO) immunoregulatory enzyme that converts the tryptophan amino acid into kynurenine. This process suppresses conventional T cell activity and drives the development of Tregs. The molecular mechanisms utilized by melanomas and other solid tumors to promote this DC tolerization process remain unknown. Previous work has shown that melanomas express high levels of several Wnt ligands and that Wnt5a expression has been associated with a poor prognosis. We have determined that Wnt5a is the dominant factor driving DC-dependent differentiation and expansion of Tregs within the melanoma microenvironment. Although this process is partially dependent on Wnt5a-mediated upregulation of DC IDO expression, our preliminary data now suggests that this DC tolerization program is comprised of additional alterations in DC metabolism. We are now proposing a strategy to extend these studies by 1) characterizing the effect that this novel Wnt5a-ß-catenin-dependent pathway has on anti-melanoma immunity and melanoma progression, 2) determining if the Wnt5a-ß-catenin signaling pathway contributes to immunotherapy resistance and whether this process can be pharmacologically reversed, and 3) elucidating the metabolic alterations induced by Wnt5a in DCs and how these metabolic changes contribute to generating an immunotolerant microenvironment. To achieve these aims, we plan to utilize a genetically engineered mouse model that physiologically resembles human melanoma and allows for a more in-depth analysis of the interplay between a developing malignancy and the local immune response. This project seeks to define a novel immune evasion pathway and, in doing so, offers a strategy to both enhance the efficacy of currently available immunotherapy approaches and broaden the patient population that may benefit from tumor immunotherapy.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Brent Allen Hanks其他文献
Brent Allen Hanks的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Brent Allen Hanks', 18)}}的其他基金
Role of the tumor NLRP3 inflammasome in the generation of anti-PD-1 antibody immunotherapy-associated toxicities
肿瘤NLRP3炎性体在抗PD-1抗体免疫治疗相关毒性产生中的作用
- 批准号:
10263391 - 财政年份:2021
- 资助金额:
$ 16.51万 - 项目类别:
Role of the tumor NLRP3 inflammasome in the generation of anti-PD-1 antibody immunotherapy-associated toxicities
肿瘤NLRP3炎性体在抗PD-1抗体免疫治疗相关毒性产生中的作用
- 批准号:
10454406 - 财政年份:2021
- 资助金额:
$ 16.51万 - 项目类别:
Role of the tumor NLRP3 inflammasome in the generation of anti-PD-1 antibody immunotherapy-associated toxicities
肿瘤NLRP3炎性体在抗PD-1抗体免疫治疗相关毒性产生中的作用
- 批准号:
10679040 - 财政年份:2021
- 资助金额:
$ 16.51万 - 项目类别:
Investigating the PD-L1:NLRP3 signaling axis as a tumor intrinsic mechanism of adaptive resistance to anti-PD-1 antibody immunotherapy
研究 PD-L1:NLRP3 信号轴作为肿瘤对抗 PD-1 抗体免疫治疗适应性耐药的内在机制
- 批准号:
10670285 - 财政年份:2020
- 资助金额:
$ 16.51万 - 项目类别:
Investigating the PD-L1:NLRP3 signaling axis as a tumor intrinsic mechanism of adaptive resistance to anti-PD-1 antibody immunotherapy
研究 PD-L1:NLRP3 信号轴作为肿瘤对抗 PD-1 抗体免疫治疗适应性耐药的内在机制
- 批准号:
10524203 - 财政年份:2020
- 资助金额:
$ 16.51万 - 项目类别:
Investigating the PD-L1:NLRP3 signaling axis as a tumor intrinsic mechanism of adaptive resistance to anti-PD-1 antibody immunotherapy
研究 PD-L1:NLRP3 信号轴作为肿瘤对抗 PD-1 抗体免疫治疗适应性耐药的内在机制
- 批准号:
10459344 - 财政年份:2020
- 资助金额:
$ 16.51万 - 项目类别:
Exploration of Tumor-Intrinsic NLRP3 Signaling Regulators
肿瘤内在NLRP3信号调节因子的探索
- 批准号:
10309148 - 财政年份:2020
- 资助金额:
$ 16.51万 - 项目类别:
Investigating the PD-L1:NLRP3 signaling axis as a tumor intrinsic mechanism of adaptive resistance to anti-PD-1 antibody immunotherapy
研究 PD-L1:NLRP3 信号轴作为肿瘤对抗 PD-1 抗体免疫治疗适应性抵抗的内在机制
- 批准号:
10159222 - 财政年份:2020
- 资助金额:
$ 16.51万 - 项目类别:
Investigating the PD-L1:NLRP3 signaling axis as a tumor intrinsic mechanism of adaptive resistance to anti-PD-1 antibody immunotherapy
研究 PD-L1:NLRP3 信号轴作为肿瘤对抗 PD-1 抗体免疫治疗适应性抵抗的内在机制
- 批准号:
10388444 - 财政年份:2020
- 资助金额:
$ 16.51万 - 项目类别:
Melanoma-mediated Dendritic Cell Tolerization and Immune Evasion
黑色素瘤介导的树突状细胞耐受和免疫逃避
- 批准号:
8967743 - 财政年份:2015
- 资助金额:
$ 16.51万 - 项目类别:
相似海外基金
Pharmacological targeting of AMP-activated protein kinase for immune cell regulation in Type 1 Diabetes
AMP 激活蛋白激酶对 1 型糖尿病免疫细胞调节的药理学靶向
- 批准号:
2867610 - 财政年份:2023
- 资助金额:
$ 16.51万 - 项目类别:
Studentship
Establishing AMP-activated protein kinase as a regulator of adipose stem cell plasticity and function in health and disease
建立 AMP 激活蛋白激酶作为脂肪干细胞可塑性和健康和疾病功能的调节剂
- 批准号:
BB/W009633/1 - 财政年份:2022
- 资助金额:
$ 16.51万 - 项目类别:
Fellowship
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2021
- 资助金额:
$ 16.51万 - 项目类别:
Postdoctoral Fellowships
Metabolic control of integrin membrane traffic by AMP-activated protein kinase controls cell migration.
AMP 激活的蛋白激酶对整合素膜运输的代谢控制控制着细胞迁移。
- 批准号:
459043 - 财政年份:2021
- 资助金额:
$ 16.51万 - 项目类别:
Studentship Programs
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2020
- 资助金额:
$ 16.51万 - 项目类别:
Postdoctoral Fellowships
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
- 批准号:
10561642 - 财政年份:2019
- 资助金额:
$ 16.51万 - 项目类别:
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2019
- 资助金额:
$ 16.51万 - 项目类别:
Postdoctoral Fellowships
Treating Diabetic Inflammation using AMP-Activated Protein Kinase Activators
使用 AMP 激活的蛋白激酶激活剂治疗糖尿病炎症
- 批准号:
2243045 - 财政年份:2019
- 资助金额:
$ 16.51万 - 项目类别:
Studentship
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
- 批准号:
10359032 - 财政年份:2019
- 资助金额:
$ 16.51万 - 项目类别:
Investigating the therapeutic potential of AMP-activated protein kinase in myotonic dystrophy type 1
研究 AMP 激活蛋白激酶在 1 型强直性肌营养不良中的治疗潜力
- 批准号:
428988 - 财政年份:2019
- 资助金额:
$ 16.51万 - 项目类别:
Studentship Programs