Immune determinants of progression from Oral Epithelial Dysplasia to Oral Squamous Cell Carcinoma by precision multiplexed imaging

项目概要/摘要 在美国，口腔癌和口咽癌每年导致超过10，000人死亡。虽然 口腔鳞状细胞癌（OSCC）患者局部疾病的生存率高达80%，约 三分之二的患者临床上存在区域和远处转移，5年生存率为50% 分别为35%。尽管免疫治疗取得了进展，但OSCC的五年死亡率仍然很高。 在过去几十年中，这种情况一直存在，突出了早期发现和干预的重要性。 大多数OSCC是由称为口腔上皮发育不良（OED）的癌前病变引起的， 其中一些会发展为侵袭性癌症。将进展的OED患者可能会受益于 早期更积极的治疗;然而，与积极治疗相关的发病率 这是非常重要的，阻止了它们在所有患者中的广泛使用。虽然这种总体前景在许多癌症中是相似的， 口腔病变的可及性也为详细分析提供了独特的机会， 有助于或防止进展为侵袭性和恶性癌症的生物过程。 我们将检验对OED的免疫反应调节进展风险的假设。 免疫系统对组织中的破坏和危险做出反应。重要的证据表明， 免疫系统在口腔早期病变中的作用，包括大量的免疫球蛋白， 细胞浸润这些组织，免疫抑制个体的风险增加，以及MHC I类抗原的丢失 在许多口腔鳞状细胞癌肿瘤中的表现机制。然而，免疫反应的特征目前还不清楚 用于定义治疗策略或对OED或OSCC患者的风险进行分层， 机会多路复用离子束成像（MIBI）的最新发展使得能够进行前所未有的详细的成像。 档案病理组织的分析。这项技术，我们最近实施的帮助下， 美国国立卫生研究院仪器资助，使用与重金属报告离子结合的抗体定量多达50种蛋白质 同时在福尔马林固定的石蜡包埋组织中以亚细胞（400 nm）分辨率进行。我们整理 大量来自OED患者的存档组织，具有详细的临床和随访数据，包括 发展为OSCC。在这里，我们将利用MIBI对这些疾病中的免疫反应进行详细分析。 肿瘤，提供了新的见解免疫机制和细胞相互作用，在这些 微环境在目标1中，我们将检验存在的免疫细胞类型及其 在继续进行的OED与没有进行的OED之间，激活状态是不同的。在目标2中， 我将检验这一假设，即在OED中，组织内的结构和细胞邻近区是不同的 发展成口腔鳞状细胞癌在目标3中，我们将使用这些数据来识别与 预测进展的风险。这些研究将利用一种新的成像技术来回答基本的 关于免疫反应的问题，并指导OED患者的精确治疗决策。

PROJECT SUMMARY/ABSTRACT Oral and oropharyngeal cancers result in over 10,000 deaths each year in the United States. Although oral squamous cell carcinoma (OSCC) patients with localized disease have survival rates of up to 80%, about two-thirds present clinically with regional and distant metastases associated with five-year survival rates of 50% and 35%, respectively. Despite advances in immunotherapy, the five-year mortality rate for OSCC has remained constant over the last several decades, underscoring the importance of early detection and intervention. The majority of OSCCs arise from pre-cancerous lesions called oral epithelial dysplasias (OED), only some of which will progress to invasive cancers. Patients with OEDs that will progress would likely benefit from more aggressive treatment early on; however, the morbidities associated with aggressive treatment are significant, preventing their broad use in all patients. While this general outlook is similar across many cancers, the accessibility of oral cavity lesions also provides a unique opportunity for detailed analysis to understand the biological processes that contribute to or protect against progression into invasive and malignant cancer. We will test the hypothesis that the immune response to OED regulates the risk of progression. The immune system responds to disruptions and danger in tissues. Significant evidence supports the important role of the immune system in responding to early lesions in the oral cavity, including an abundance of immune cells infiltrating these tissues, elevated risk in immunosuppressed individuals, and loss of MHC class I antigen presentation machinery in many OSCC tumors. However, features of the immune response are not currently utilized to define treatment strategies or to stratify risk in OED or OSCC patients, presenting an unmet opportunity. The recent development of multiplexed ion beam imaging (MIBI) enables unprecedented detailed analysis of archival pathological tissues. This technology, which we recently implemented with the help of an NIH Instrumentation Grant, uses antibodies conjugated to heavy-metal reporter ions to quantify up to 50 proteins simultaneously at subcellular (400nm) resolution in formalin-fixed paraffin-embedded tissues. We have collated a substantial number of archival tissues from OED patients with detailed clinical and follow up data, including progression to OSCC. Here, we will leverage MIBI to conduct a detailed analysis of immune responses in these tumors, providing new insight into the immunological mechanisms and cellular interactions in these microenvironments. In Aim 1, we will test the hypothesis that the types of immune cells present and their activation states are distinct between OEDs that went on to progress versus those that have not. In Aim 2, we will test the hypothesis that the architecture and cellular neighborhoods within the tissue are distinct in OEDs that progressed to OSCC. In Aim 3, we will use these data to identify immune features associated with and predictive of risk of progression. These studies will harness a new imaging technique to answer fundamental questions about the immune response and to guide precise treatment decisions for patients with OED.