NLR and Oral Cancer Immune Escape
NLR 与口腔癌免疫逃逸
基本信息
- 批准号:9755594
- 负责人:
- 金额:$ 3.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-03-01 至 2022-02-28
- 项目状态:已结题
- 来源:
- 关键词:AftercareAgonistAntigen PresentationBindingBone MarrowCD8-Positive T-LymphocytesCD8B1 geneCancer BiologyCancer cell lineCell MaturationCell-Mediated CytolysisCellsCellular ImmunityComorbidityCytotoxic T-LymphocytesDataDeglutition DisordersDendritic CellsDetectionExhibitsGene ExpressionGenesGeneticGoalsHead and Neck CancerHead and Neck Squamous Cell CarcinomaHumanHuman papilloma virus infectionImmuneImmune checkpoint inhibitorImmune responseImmune signalingImmunologic MonitoringImmunologicsImmunologyImmunosuppressionImmunosuppressive AgentsImmunotherapeutic agentImmunotherapyImplantIncidenceInterferon Type IInterferonsLeadershipLeucine-Rich RepeatLinkLymphocyteMalignant Epithelial CellMalignant NeoplasmsMediatingModelingMusMutationMyeloid CellsNatural ImmunityNucleotidesOral healthOsteoradionecrosisOutcomePPBP genePathologyPathway interactionsPatientsPhenotypeRegulationResearchResistanceRoleSignal PathwaySignal TransductionStimulator of Interferon GenesTestingTreatment ProtocolsTumor BurdenTumor EscapeTumor ImmunityTumor-infiltrating immune cellsUnited StatesVaccinescancer cellcombatexperimental studygenetic signatureimmune checkpoint blockadeimmunogenicimprovedin vivoinsightleucine-rich repeat proteinmacrophagemalignant mouth neoplasmnanoparticleneoantigensoutcome forecastpolarized cellreceptorresponsestandard caretargeted deliverytargeted treatmenttraffickingtumortumor microenvironmenttumorigenicvaccine efficacy
项目摘要
PROJECT SUMMARY
The incidence rates of head and neck squamous cell carcinoma (HNSCC) in the United States have
quadrupled in the past several decades. The current standard treatment regimen is associated with significant
co-morbidities such as dysphagia and osteoradionecrosis. The mechanisms underlying poor immunological
host responses are multifactorial, and the most significant challenge is that HNSCC contains few tumor-
specific cytotoxic T lymphocytes in the tumor microenvironment (TME), despite abundant mutations. Data from
our group suggests that type I interferon (IFN-I) signaling in HNSCC patients is critically associated with a
Tc1/TH1-skewed TME and superior patient prognosis. Indeed, stimulator of interferon inducible genes
(STING)-mediated IFN-I signaling has proven a central mechanism in facilitating CD8+ T-cell expansion.
However, the STING pathway is frequently suppressed in cancers, and the mechanisms underlying type I
interferon signaling remain insufficiently characterized.
Preliminary data from our lab has shown that the regulatory nucleotide-binding domain and leucine rich repeat
(NLR) protein NLRC3, which has been previously characterized as a negative regulator of type I interferon
signaling in myeloid cells, is upregulated in human HNSCC cells resistant to cell-mediated cytotoxicity,
indicating its potential role in mediating cancer immunosuppression. Therefore, the first aim of this project is to
elucidate how NLRC3 modulates tumor and host-intrinsic type I interferon signaling in head and neck cancer
pathology. The second aim of this project will investigate the immunological mechanisms which influence
cytotoxic T cell infiltration into tumors post-treatment with activators of STING-dependent type I interferon
signaling. Given the central role of M1-like macrophages and CD8a+ dendritic cells in promoting CD8+ T-cell
maturation, the experiments proposed will likely provide a critical link in combating oral cancer
immunosuppression.
This proposal will be conducted under the guidance of Dr. Lei and Dr. Chen, whose combined expertise in
immunology, cancer biology, and oral health will provide crucial leadership for the execution the proposed
experiments.
项目摘要
美国头颈部鳞状细胞癌(HNSCC)的发病率
在过去的几十年里翻了两番。目前的标准治疗方案与显著的
合并症,如吞咽困难和放射性骨坏死。免疫功能低下的机制
宿主反应是多因素的,最重要的挑战是HNSCC包含很少的肿瘤-
肿瘤微环境(TME)中的特异性细胞毒性T淋巴细胞,尽管有丰富的突变。数据从
我们的研究小组表明,HNSCC患者的I型干扰素(IFN-I)信号传导与HNSCC患者的免疫功能密切相关。
Tc 1/TH 1-偏斜TME和上级患者预后。事实上,干扰素诱导基因的刺激物
(STING)介导的IFN-I信号传导已被证明是促进CD 8 + T细胞扩增的中心机制。
然而,STING通路在癌症中经常被抑制,并且I型糖尿病的潜在机制是
干扰素信号传导仍然没有充分表征。
我们实验室的初步数据表明,调节核苷酸结合结构域和富含亮氨酸的重复序列
(NLR)蛋白质NLRC 3,其先前已被表征为I型干扰素的负调节剂
骨髓细胞中的信号传导,在对细胞介导的细胞毒性有抗性的人HNSCC细胞中上调,
表明其在介导癌症免疫抑制中的潜在作用。因此,本项目的首要目标是
阐明NLRC 3如何调节头颈癌中肿瘤和宿主内源性I型干扰素信号传导
病理本项目的第二个目的是研究影响免疫功能的免疫机制。
STING依赖性I型干扰素激活剂治疗后细胞毒性T细胞浸润到肿瘤中
发信号。考虑到M1样巨噬细胞和CD 8a+树突状细胞在促进CD 8 + T细胞增殖中的核心作用,
成熟,提出的实验可能会提供一个关键环节,在打击口腔癌
免疫抑制
本提案将在雷博士和陈博士的指导下进行,他们在以下方面的综合专业知识
免疫学、癌症生物学和口腔健康将为执行拟议的
实验
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)
专利数量(0)
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Blake Heath的其他文献
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