Analysis of the E7-Mediated Mechanism of MHC Class I Repression in HNSCC
E7 介导的 HNSCC I 类 MHC 抑制机制分析
基本信息
- 批准号:10434757
- 负责人:
- 金额:$ 3.62万
- 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:2020-07-01 至 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAcetylationAddressAlanineAntitumor ResponseArchitectureAutoantigensBindingBinding SitesBiological AssayCD3 AntigensCD8-Positive T-LymphocytesCD8B1 geneCRISPR/Cas technologyCell LineCellsCessation of lifeChIP-seqChromatinChromatin StructureClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCoculture TechniquesCytotoxic T-LymphocytesDNADataDetectionDiseaseEtiologyFlow CytometryGene Expression RegulationGenesGeneticGenetic TranscriptionGoalsHLA-A geneHPV-High RiskHead and Neck Squamous Cell CarcinomaHuman PapillomavirusHuman papillomavirus 16Human papillomavirus 18ImmuneImmune EvasionImmunotherapyIncidenceInterferon Type IIKnock-outMHC Class I GenesMajor Histocompatibility ComplexMalignant NeoplasmsMass Spectrum AnalysisMediatingModelingMolecularOncogenicOncoproteinsOrganoidsPathogenicityPathway interactionsPatientsPeripheral Blood Mononuclear CellPharmacologic SubstanceProductionProteinsRNA Polymerase IIRegulationRegulatory PathwayRepressionScanningSiteStainsSurfaceT-Cell ActivationT-LymphocyteTestingTherapeuticTranscriptional RegulationTransfectionUnited StatesValidationWorkanti-tumor immune responsebasecancer typegenome-widegenomic locushuman old age (65+)improvedinhibitorknockout genemalignant oropharynx neoplasmneoantigensneoplastic cellnew therapeutic targetnovelnovel therapeutic interventionoverexpressionprevent
项目摘要
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type in the world, and is
responsible for over 8,000 deaths in the United States each year. The number of HNSCC cases caused by
human papilloma virus (HPV) is on the rise, especially in patients 40-65 years old. HPV is currently associated
with 80% of oropharyngeal cancers and 5-10% of HNSCC cases from other sub-sites. High-risk HPV strains,
most commonly HPV16 and HPV18, cause the preponderance of HPV-positive HNSCC. Current data suggests
that in HNSCC, HPV16 limits immune detection by preventing surface presentation of the major
histocompatibility complex class I (MHC-I). In HPV-positive HNSCC, MHC-I surface presentation level is
associated with the cytotoxic T cell-mediated anti-tumor immune response and thus the identification of
strategies to prevent HPV-mediated MHC-I repression may have a significant therapeutic benefit for patients
receiving immunotherapies. There some data that suggest E7 negatively regulates transcription of MHC-I
constituent genes; however, the detailed mechanism of E7-mediated MHC-I repression is poorly characterized.
Here, I have generated two E7-overexpressing HPV-negative HNSCC cell lines and confirmed that E7 protein
downregulates transcription of MHC-I. We have developed systematic and logical approaches including
CRISPR/CAS9 profiling that we propose to leverage to characterize the molecular mechanism(s) by which E7-
represses MHC-I in these models, and HPV+ HNSCC models. Further, we have developed a 3D organoid-based
co-culture assay in which these models are co-cultured with patient-matched peripheral blood mononuclear cells
(PBMCs) to test the functional effects of de-repression of MHC-I expression. My central hypothesis is that
identification of the molecular mechanisms by which HPV16_E7 diminish the expression of MHC-I will
lead to the advancement of therapeutic strategies that enhance tumor cell recognition by activated T-
cells. I will address this hypothesis through the following aims: 1) Detail the molecular mechanism(s) of MHC
locus repression by HPV16_E7 in HNSCC, and 2) Qualify HPV16_E7-dependent MHC class I regulatory
pathways in HNSCC. My long-term goal is to develop new therapeutic approaches that improve the overall
survival of HPV+ patients, and in doing so, I hope to characterize the specific mechanisms by which HPV16_E7
can prevent MHC-I surface expression in HPV-positive HNSCC.
摘要
头颈部鳞状细胞癌(HNSCC)是世界上第六大最常见的癌症类型,
美国每年有超过8,000人死于这种疾病由以下原因引起的HNSCC病例数
人乳头瘤病毒(HPV)感染呈上升趋势,尤其是在40-65岁的患者中。HPV目前与
80%的口咽癌和5-10%的HNSCC病例来自其他亚位点。高危HPV病毒株,
最常见的HPV 16和HPV 18引起HPV阳性HNSCC的优势。目前的数据显示,
在HNSCC中,HPV 16通过阻止HPV 16主要抗原的表面呈递来限制免疫检测。
组织相容性复合物I类(MHC-I)。在HPV阳性的HNSCC中,MHC-I表面呈递水平是
与细胞毒性T细胞介导的抗肿瘤免疫应答相关,
预防HPV介导的MHC-I抑制的策略可能对患者具有显著的治疗益处
接受免疫治疗有资料表明E7负调控MHC-I的转录
然而,E7介导的MHC-I抑制的详细机制的特点很差。
在这里,我已经建立了两个E7过表达HPV阴性的HNSCC细胞系,并证实E7蛋白
下调MHC-I的转录。我们已经制定了系统和逻辑的方法,包括
我们建议利用CRISPR/CAS9分析来表征E7-
在这些模型和HPV+ HNSCC模型中抑制MHC-I。此外,我们还开发了一种基于3D类器官的
共培养试验,其中这些模型与患者匹配的外周血单核细胞共培养
(外周血单个核细胞)来测试MHC-I表达去抑制的功能影响。我的核心假设是
HPV16_E7减少MHC-I表达的分子机制的鉴定将
导致治疗策略的进步,通过活化的T-
细胞本文将从以下几个方面对这一假说进行阐述:1)阐明MHC的分子机制
HNSCC中HPV16_E7的基因座阻遏,和2)鉴定HPV16_E7依赖性MHC I类调节基因
HNSCC中的通路。我的长期目标是开发新的治疗方法,
HPV+患者的生存率,在这样做的过程中,我希望描述HPV16_E7
可抑制HPV阳性HNSCC中MHC-I表面表达。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Integrative sequencing discovers an ATF1-motif enriched molecular signature that differentiates hyalinizing clear cell carcinoma from mucoepidemoid carcinoma.
- DOI:10.1016/j.oraloncology.2021.105270
- 发表时间:2021-06
- 期刊:
- 影响因子:4.8
- 作者:Heft Neal ME;Gensterblum-Miller E;Bhangale AD;Kulkarni A;Zhai J;Smith J;Brummel C;Foltin SK;Thomas D;Jiang H;McHugh JB;Brenner JC
- 通讯作者:Brenner JC
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Elizabeth Gensterblum-Miller其他文献
Elizabeth Gensterblum-Miller的其他文献
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{{ truncateString('Elizabeth Gensterblum-Miller', 18)}}的其他基金
Analysis of the E7-Mediated Mechanism of MHC Class I Repression in HNSCC
E7 介导的 HNSCC I 类 MHC 抑制机制分析
- 批准号:
10219154 - 财政年份:2020
- 资助金额:
$ 3.62万 - 项目类别:
Analysis of the E7-Mediated Mechanism of MHC Class I Repression in HNSCC
E7 介导的 HNSCC I 类 MHC 抑制机制分析
- 批准号:
10066535 - 财政年份:2020
- 资助金额:
$ 3.62万 - 项目类别:
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