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Robust Immuno-prevention Strategies for High-Risk Oral Epithelial Dysplasia

针对高风险口腔上皮发育不良的强有力的免疫预防策略

基本信息

批准号：
10384385
负责人：
John Chadwick Brenner
金额：
$ 15.89万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-06 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10384385
关键词：
3q26 Address Agonist Automobile Driving Bypass Cells Chromosomes Clinical Collection Cross-Priming Cytotoxic T-Lymphocytes Dendritic Cells Disadvantaged Disease Disease model Effector Cell Epithelial Erythroplasia Esophageal carcinoma Event Excision Exhibits Gene Expression Profile Genetically Engineered Mouse Genomics Glucose Glycolysis Glycolysis Pathway Goals Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Histologic Human Hypoxia Immune Immune Targeting Immune response Immunity Immunologic Surveillance Immunologics Immunoprevention Immunosuppression Immunotherapy Infiltration Interferon Type I Interferons Intraepithelial Neoplasia Lead Lesion Longitudinal cohort Lymphocyte Malignant - descriptor Malignant Neoplasms Mediating Metabolic Metabolic stress Modeling Molecular Profiling Morbidity - disease rate Mucous Membrane Oncogenes Oncogenic Operative Surgical Procedures Oral Oral Leukoplakia PIK3CA gene Pathway interactions Patients Pharmaceutical Preparations Prevention Public Health Regimen Resolution Signal Transduction Skin Carcinoma Specimen Squamous Cell Lung Carcinoma Stains Subgroup T-Lymphocyte Testing Time Tumor Burden Tumor-infiltrating immune cells Warburg Effect cancer cell case control combinatorial cytotoxic CD8 T cells design effective therapy extracellular head and neck cancer patient high risk high risk population human disease immune activation immune checkpoint blockade improved in vivo individualized medicine inhibitor/antagonist innate immune sensing loss of function malignant mouth neoplasm mutant novel novel therapeutics oral cavity epithelium orofacial premalignant prevent programs public health relevance recruit response restraint tumor tumor hypoxia tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY Immune checkpoint blockade has proven an effective treatment for a subset of head and neck cancer (HNC) patients. However, over 85% of the patients cannot benefit from this strategy, largely due to the highly immunosuppressive tumor microenvironment (TME) in established cancers. Oral leukoplakias / Oral Epithelial Dysplasias (OEDs) precede HNC and offer a unique time window for disease eradication. However, surgical resection in the orofacial region results in significant morbidity and function loss, and more importantly, cannot reverse field cancerization. A subset of OEDs transform into malignancy despite vigilant follow-ups. Frequent immune cell infiltration is a common feature of OEDs, however, little is known about when and how OEDs evade from immuno-surveillance and reach a point-of-no-return. In addition, it remains unclear which sub- group of OEDs is more likely to suppress host immunity and establish themselves as high-risk lesions. Amplification of the chromosome locus 3q26.3 is a defining genomic feature of HNC, and two oncogenes at this locus inhibit innate immune sensing pathways and elicit a metabolic restraint in the TME, which collectively disadvantage anti-tumor immune cells. We have developed strategies to bypass the inhibition of innate immune sensing and synthesized a novel drug-like molecule that exhibits potent metabolic remodeling potential and anti-tumor activity in vivo. We constructed two unique genetically engineered mouse models, which can model a spectrum of OED/HNC lesions with high-fidelity histologic and immunophenotypic resemblance to human diseases, to recapitulate 3q26.3-driven OED transformation. We also identified unique collections of case-control and longitudinal paired OED/HNC specimens, which allow us to validate key findings on the temporal shift of exploitable immune targets with clinical specimens. The overarching goal of this translational program is to test the hypothesis that 3q26.3 amplification is a key early high-risk event that leads to OED immune escape and that a combination of metabolic remodeling agent with immunotherapy effectively prevents OED progression. Thus, this proposal is fully responsive to the RFA-CA-19-014 and is focused on the deeper understanding of the time-course of immune landscape shift as pre-malignant lesions progress, using 3q26.3 amplification-driven OEDs as a high-risk disease model. We will qualify a novel metabolic remodeling drug-like molecule as a priming agent to maximally improve immuno-prevention. The 3q26.3 amplification is not unique to HNC and commonly found in squamous cell carcinomas of the lung, esophagus and skin, hence, our findings will help address a broad class of public health concerns.

项目总结免疫检查点阻断已被证明是治疗头颈癌的一种有效方法 (HNC)患者。然而，超过85%的患者无法从这一策略中受益，这主要是由于高度已确诊癌症的免疫抑制肿瘤微环境(TME)。口腔白斑/口腔上皮发育不良(OED)先于HNC，为根除疾病提供了独特的时间窗口。然而，外科手术切除口腔面部会导致严重的并发症和功能丧失，更重要的是，不能逆野癌变。尽管有警惕的后续行动，OEDs的一部分仍会转化为恶性肿瘤。频密免疫细胞渗透是OEDs的一个共同特征，然而，对OEDs的时间和方式知之甚少逃避免疫监控，走上不归路。此外，目前仍不清楚是哪一家子公司 OED组更有可能抑制宿主免疫，并将自己确立为高危病变。染色体3q26.3位点的扩增是HNC的一个决定性基因组特征，两个癌基因位于该基因座抑制先天免疫感知通路，并在TME中引起代谢抑制，这些共同作用对抗肿瘤免疫细胞不利。我们已经开发出了绕过先天抑制的策略免疫传感和合成了一种新的类药物分子，显示出强大的代谢重塑体内潜在的抗肿瘤活性。我们构建了两个独特的基因工程小鼠模型，它可以用高保真的组织学和免疫表型来模拟OED/HNC皮损的频谱与人类疾病相似，概括一下3q26.3驱动的OED转变。我们还确定了唯一的病例对照和纵向配对的OED/HNC标本集合，使我们能够验证临床标本中可利用免疫靶点时间移位的发现。的首要目标是此翻译程序旨在验证3q26.3扩增是关键的早期高危事件的假设导致OED免疫逃逸，代谢重建剂与免疫治疗相结合有效地防止牛津英语学习障碍的进展。因此，本提案完全响应RFA-CA-19-014，重点是对免疫格局作为癌前病变的时间进程的更深层次的理解进展，使用3q26.3扩增驱动的OEDs作为高危疾病模型。我们将把一部小说定为合格小说代谢重塑类药物分子作为引发剂，最大限度地提高免疫预防能力。这个 3q26.3扩增不是HNC特有的，通常见于肺鳞状细胞癌，因此，我们的发现将有助于解决广泛的公共卫生问题。