Mapping immuno-genomic drivers of the head and neck precancer invasive-disease transition

项目总结 全球有90多万人被诊断为头颈部鳞状细胞癌(HNSCC) 去年，每年有超过25万人死于这种癌症。感染人乳头瘤病毒(HPV) 已知的发生HNSCC的危险因素，显著影响临床预后。具体地说，对于HPV- 阴性的HNSCC是头颈癌中最致命的亚型，确诊的患者中存活的不到30% 已经五年多了。最常见和致命的HPV阴性的HNSCC亚型是口腔鳞状细胞癌 细胞癌(OSCC)重要的是，大多数口腔鳞状细胞癌之前都有形态上可区分的前 易于进行组织学和分子评估的癌性病变。这提供了一种独特的 通过停止转化，在这种致命的癌症发展的最早阶段拦截它的机会 口腔癌前病变转化为侵袭性口腔鳞癌。口腔白斑，这一应用的重点，代表了最常见的 口腔癌前病变类型，每50个人中就有一个人预计会在其一生中患上口腔扁平苔藓。OL低迷 进展为口腔癌的约3.3%的恶变率及其高度可变的自然病史构成了 调查口腔扁平苔藓及其恶性转化为浸润性口腔癌的主要挑战。 为了应对这一挑战，我们假设从OL到OSCC的进化过渡是由于 免疫-基因组相互作用包括获得体细胞驱动事件，获得 染色体不稳定，以及失去有效的免疫监控。我们进一步假设基因组 而随后发展为口腔癌(进展期)的患者的OL免疫状况将不同于 那些没有患口腔癌的人(非进展者)。这个项目的总体目标是阐明 口腔扁平苔藓进展为口腔鳞状细胞癌的分子和免疫机制，并形成可操作和可预测的机制 生物标志物。为了实现这一目标，我们将利用经过良好注释的OL队列来生成最大的整体- 外显子组和整个转录组图谱，包括300个OL，包括至少100个癌症进展和 100个非进步者。进一步地，通过利用空间多重免疫荧光平台和无偏向 RNA测序方法用于免疫图谱，我们将全面绘制这些 300个口腔鳞状细胞癌，并将不同的免疫遗传学特征与可能进展为口腔鳞癌相关联。最后，我们的状况- ART口腔癌变小鼠模型将用于在单个细胞上模拟OL向OSCC的转变 为了了解常见的基因组改变和免疫监测在这一过程中的作用 进程。总体而言，这个项目将揭示推动进化的免疫遗传变化的概要。 从口腔鳞癌向口腔鳞状细胞癌的转变及一组靶向免疫细胞群的阐明(S)和新免疫 监督机制，这很可能阻止这种恶变。

PROJECT SUMMARY Globally, more than 900,000 people are diagnosed with head and neck squamous cell carcinoma (HNSCC) each year, with more that 250,000 dying annually from this cancer. Infection with human papilloma virus (HPV), a known risk factor for developing HNSCC, significantly impacts clinical prognostication. Specifically, for HPV- negative HNSCC, the most lethal subtype of head and neck cancer, less than 30% of those diagnosed survive for more than five years. The most common and lethal HPV-negative HNSCC subtype is oral cavity squamous cell carcinoma (OSCC). Importantly, most OSCCs are preceded by morphologically distinguishable pre- cancerous lesions which are readily accessible for histological and molecular evaluation. This provides a unique opportunity for intercepting this deadly cancer in the earliest stages of its development by halting the conversion of oral precancer into invasive OSCC. Oral leukoplakia, the focus of this application, represents the most frequent type of oral premalignancy, with one in every fifty people is expected to develop OL in their lifetime. OL’s low malignant transformation rate of ~3.3% progressing to oral cancer and its highly variable natural history poses a major challenge for surveying OLs and for intercepting their malignant conversion into invasive oral cancers. To address this challenge, we hypothesize that the evolutionary transition from an OL into an OSCC is due to the immuno-genomic interactions encompassing the acquisition of somatic driver events, the gain of chromosomal instability, and the loss of effective immunosurveillance. We further hypothesize that the genomic and immune landscapes of OL in patients who subsequently develop oral cancer (progressors) will differ from those that do not develop oral cancer (non-progressors). The overall objective of this project is to elucidate the molecular and immune mechanisms by which OLs progress to OSCCs, and to develop actionable and predictive biomarkers. To achieve this objective, we will leverage well-annotated OL cohorts to generate the largest whole- exome and whole-transcriptome atlas encompassing 300 OLs, including at least 100 cancer progressors and 100 non-progressors. Further, by utilizing a spatial multiplex immuno-fluorescence platform and an unbiased RNA-sequencing approach for immuno-profiling, we will comprehensively map the immune landscapes of these 300 OLs and associate distinct immuno-genetic features with likely progression to OSCC. Lastly, our state-of- the-art oral carcinogenesis mouse model will be used to model the transition of OL to OSCC at the single cell resolution in order to understand the role of common genomic alterations and immune surveillance in this process. Overall, this project will reveal the compendium of immuno-genetic changes that drive the evolutionary transition from an OL to an OSCC and elucidate a set of targetable immune cell population(s) and novel immune surveillance mechanisms, which can likely halt this malignant transformation.