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.

项目概要免疫检查点阻断已被证明是治疗部分头颈癌的有效方法（HNC）患者。然而，超过 85% 的患者无法从该策略中受益，这主要是由于高度已确定癌症中的免疫抑制肿瘤微环境（TME）。口腔白斑/口腔上皮细胞发育异常 (OED) 先于 HNC 发生，并为根除疾病提供了独特的时间窗口。然而，手术口面部区域的切除会导致严重的发病率和功能丧失，更重要的是，不能逆转区域癌化。尽管采取了警惕的后续行动，但仍有一部分 OED 会转化为恶性肿瘤。经常免疫细胞浸润是 OED 的一个常见特征，然而，人们对 OED 何时以及如何发生知之甚少逃避免疫监视并到达不归路。此外，目前尚不清楚哪个子 OED 组更有可能抑制宿主免疫并将其自身确定为高风险病变。染色体位点 3q26.3 的扩增是 HNC 的一个定义基因组特征，并且两个癌基因位于该基因座抑制先天免疫传感途径并引起 TME 中的代谢抑制，这些共同作用对抗肿瘤免疫细胞不利。我们已经开发出绕过先天抑制的策略免疫传感并合成了一种新型药物样分子，具有有效的代谢重塑作用潜在的体内活性和抗肿瘤活性。我们构建了两种独特的基因工程小鼠模型，它可以通过高保真组织学和免疫表型对一系列 OED/HNC 病变进行建模与人类疾病相似，概括 3q26.3 驱动的 OED 转化。我们还确定了独特的病例对照和纵向配对 OED/HNC 样本的收集，使我们能够验证关键关于临床样本中可利用的免疫靶标的时间变化的发现。总体目标是该转化程序旨在检验以下假设：3q26.3 扩增是一个关键的早期高风险事件，导致 OED 免疫逃逸，代谢重塑剂与免疫疗法的结合有效防止 OED 进展。因此，该提案完全响应 RFA-CA-19-014，并且重点是更深入地了解作为癌前病变的免疫景观转变的时间过程进展，使用 3q26.3 扩增驱动的 OED 作为高风险疾病模型。我们将鉴定一部小说代谢重塑药物样分子作为引发剂，最大限度地改善免疫预防。这 3q26.3 扩增并非 HNC 所独有，也常见于肺鳞状细胞癌，食道和皮肤，因此，我们的研究结果将有助于解决广泛的公共卫生问题。