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: 10434757
• 负责人: Elizabeth Gensterblum-Miller
• 金额: $ 3.62万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10434757
• 关键词: 3-Dimensional; Acetylation; Address; Alanine; Antitumor Response; Architecture; Autoantigens; Binding; Binding Sites; Biological Assay; CD3 Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; CRISPR/Cas technology; Cell Line; Cells; Cessation of life; ChIP-seq; Chromatin; Chromatin Structure; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Cytotoxic T-Lymphocytes; DNA; Data; Detection; Disease; Etiology; Flow Cytometry; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Goals; HLA-A gene; HPV-High Risk; Head and Neck Squamous Cell Carcinoma; Human Papillomavirus; Human papillomavirus 16; Human papillomavirus 18; Immune; Immune Evasion; Immunotherapy; Incidence; Interferon Type II; Knock-out; MHC Class I Genes; Major Histocompatibility Complex; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Oncogenic; Oncoproteins; Organoids; Pathogenicity; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmacologic Substance; Production; Proteins; RNA Polymerase II; Regulation; Regulatory Pathway; Repression; Scanning; Site; Stains; Surface; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Transcriptional Regulation; Transfection; United States; Validation; Work; anti-tumor immune response; base; cancer type; genome-wide; genomic locus; human old age (65+); improved; inhibitor; knockout gene; malignant oropharynx neoplasm; neoantigens; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; overexpression; prevent

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

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: Oral oncology
• 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