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
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
{{
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 }}
Elizabeth Gensterblum-Miller其他文献
Elizabeth Gensterblum-Miller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('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:
相似海外基金
Investigating the functions of histone acetylation in genome organization and leukemogenesis
研究组蛋白乙酰化在基因组组织和白血病发生中的功能
- 批准号:
EP/Y000331/1 - 财政年份:2023
- 资助金额:
$ 3.62万 - 项目类别:
Research Grant
Gene Modulation of Acetylation Modifiers to Reveal Regulatory Links to Human Cardiac Electromechanics
乙酰化修饰剂的基因调节揭示与人类心脏机电的调节联系
- 批准号:
10677295 - 财政年份:2023
- 资助金额:
$ 3.62万 - 项目类别:
Novel roles of PDK2 in heart failure: Regulation of mitochondrial nuclear crosstalk via metabolic regulation and histone acetylation
PDK2 在心力衰竭中的新作用:通过代谢调节和组蛋白乙酰化调节线粒体核串扰
- 批准号:
10635599 - 财政年份:2023
- 资助金额:
$ 3.62万 - 项目类别:
Regulation of hepatic lysine N-acetylation by cysteine proximity due to alcohol toxicity
酒精毒性导致的半胱氨酸接近对肝脏赖氨酸 N-乙酰化的调节
- 批准号:
10752320 - 财政年份:2023
- 资助金额:
$ 3.62万 - 项目类别:
Histone Acetylation Regulates Microglial Innate Immune Memory
组蛋白乙酰化调节小胶质细胞先天免疫记忆
- 批准号:
478927 - 财政年份:2023
- 资助金额:
$ 3.62万 - 项目类别:
Operating Grants
Dysregulation of Histone Acetylation in Parkinson's Disease
帕金森病中组蛋白乙酰化的失调
- 批准号:
10855703 - 财政年份:2023
- 资助金额:
$ 3.62万 - 项目类别:
Obesity-related hypertension: the contribution of PPAR gamma acetylation and asprosin
肥胖相关高血压:PPAR γ 乙酰化和白脂素的贡献
- 批准号:
10654210 - 财政年份:2023
- 资助金额:
$ 3.62万 - 项目类别:
The role N-terminal acetylation in dilated cardiomyopathy and associated arrhythmia
N-末端乙酰化在扩张型心肌病和相关心律失常中的作用
- 批准号:
10733915 - 财政年份:2023
- 资助金额:
$ 3.62万 - 项目类别:
In vivo tracing of hepatic ethanol metabolism to histone acetylation: role of ACSS2 in alcohol-induced liver injury
肝脏乙醇代谢与组蛋白乙酰化的体内追踪:ACSS2 在酒精性肝损伤中的作用
- 批准号:
10667952 - 财政年份:2023
- 资助金额:
$ 3.62万 - 项目类别:
The function of TWIST1 acetylation in cell fate and tissue development
TWIST1 乙酰化在细胞命运和组织发育中的作用
- 批准号:
10726986 - 财政年份:2023
- 资助金额:
$ 3.62万 - 项目类别:














{{item.name}}会员




