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.

项目摘要免疫检查点封锁已证明对头部和颈癌的一部分有效治疗（HNC）患者。但是，超过85％的患者无法从这种策略中受益，这主要是由于高度造成的已建立的癌症中的免疫抑制肿瘤微环境（TME）。口服白细胞 /口腔上皮发育不良（OEDS）先于HNC，并为消除疾病提供了独特的时间窗口。但是，手术口面区域的切除会导致明显的发病率和功能丧失，更重要的是，不能反向场癌化。尽管有警惕的随访，但OED的子集转变为恶性肿瘤。频繁免疫细胞浸润是OED的共同特征，但是，关于oeds何时以及如何了解逃避免疫护理，并到达无返回点。此外，尚不清楚哪个子 OED组更有可能抑制宿主的免疫力并将自己确立为高风险病变。染色体基因座3q26.3的扩增是HNC的定义基因组特征，而在该基因座抑制先天免疫传感途径，并在TME中引起代谢约束缺点抗肿瘤免疫细胞。我们已经制定了绕过抑制先天的策略免疫传感并合成了一种新型药物样分子，该分子表现出有效的代谢重塑体内潜力和抗肿瘤活性。我们构建了两个独特的基因工程鼠标模型，可以建模具有高保真性组织学和免疫表型的OED/HNC病变与人类疾病相似，以概括3Q26.3驱动的OED转化。我们还确定了独特的病例控制和纵向配对的OED/HNC标本的集合，这使我们能够验证钥匙关于用临床标本可剥削的免疫靶标的时间转移的发现。总体目标该翻译计划是为了检验3Q26.3扩增是一个关键的早期高风险事件的假设。导致OED免疫逃逸，并将代谢重塑剂与免疫疗法的组合有效防止OED进展。因此，该建议完全响应RFA-CA-19-014，并且是专注于对免疫景观转移的时间顺序的更深入的理解，作为恶性病变进展，使用3Q26.3扩增驱动的OED作为高危疾病模型。我们将有资格一本小说代谢重塑药物样分子作为启动剂，以最大程度地改善免疫预防。这 3Q26.3扩增不是HNC独有的，并且通常在肺的鳞状细胞癌中发现，食管和皮肤，因此，我们的发现将有助于解决广泛的公共卫生问题。