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

项目摘要 免疫检查点阻断已被证明是一种有效的治疗头颈部癌症的方法 (HNC)患者然而，超过85%的患者不能从这种策略中受益，主要是由于高度的 免疫抑制肿瘤微环境（TME）在已建立的癌症中的作用。口腔白斑/口腔上皮 发育不良（OED）先于HNC，为疾病根除提供了独特的时间窗。然而，外科 口面区域的切除导致显著的发病率和功能丧失，更重要的是， 反向场癌变。一个子集的OED转化为恶性肿瘤，尽管警惕后续。频繁 免疫细胞浸润是OEDs的一个共同特征，然而，关于OEDs何时以及如何浸润却知之甚少。 逃避免疫监视，走上不归路此外，目前还不清楚是哪一个子... OED组更可能抑制宿主免疫力，并使自身成为高危病变。 染色体3q26.3位点的扩增是HNC的一个决定性基因组特征， 该基因座抑制先天性免疫传感途径，并引起TME中的代谢抑制， 不利的抗肿瘤免疫细胞。我们已经开发出了绕过先天性抑制的策略， 免疫传感，并合成了一种新的药物样分子，表现出强大的代谢重塑 潜在的和体内抗肿瘤活性。我们构建了两个独特的基因工程小鼠模型， 它可以模拟一系列具有高保真组织学和免疫表型的OED/HNC病变， 与人类疾病的相似性，以概括3q26.3驱动的OED转换。我们还发现了 病例对照和纵向配对OED/HNC标本的集合，这使我们能够验证关键 临床标本中可利用的免疫靶点的时间变化的研究结果。的首要目标 这个翻译程序是为了检验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，代谢重塑剂与免疫疗法组合 有效地阻止了OED的进展。因此，本提案完全符合RFA-CA-19-014， 重点是更深入地了解免疫景观转变为癌前病变的时间过程 进展，使用3q26.3扩增驱动的OED作为高风险疾病模型。我们要把一部小说 代谢重塑药物样分子作为引发剂以最大程度地改善免疫预防。的 3q26.3扩增并非HNC所独有，通常见于肺鳞状细胞癌， 因此，我们的研究结果将有助于解决广泛的公共卫生问题。

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.