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

通过精密多重成像研究从口腔上皮发育不良到口腔鳞状细胞癌进展的免疫决定因素

• 批准号: 10646294
• 负责人: Matthew Spitzer
• 金额: $ 73.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646294
• 关键词: Adopted; Affect; Antigen Presentation; Architecture; Benign; Biological Factors; Biological Process; Biopsy; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Proliferation; Cell physiology; Cells; Cessation of life; Chronic; Clinical; Clinical Data; Complex; Data; Dendritic Cells; Development; Diagnosis; Disease; Distant Metastasis; Early Diagnosis; Early Intervention; Early treatment; Elements; Epithelial Cells; Erythroplasia; Exhibits; Formalin; Future; Grant; Heavy Metals; Histocompatibility Antigens Class I; Histologic; Human; Imaging Techniques; Immune; Immune response; Immune system; Immunologics; Immunotherapy; Individual; Inflammation; Inflammatory; Interferons; Intraepithelial Neoplasia; Ions; Lesion; Localized Disease; Lymphocyte; Macrophage; Malignant - descriptor; Malignant Neoplasms; Measurement; Mediating; Microscopic; Modeling; Molecular; Morbidity - disease rate; Multiplexed Ion Beam Imaging; Mus; Mutate; Mutation; Myeloid Cells; Neighborhoods; Oral Leukoplakia; Oral cavity; Paraffin Embedding; Pathologic; Patients; Persons; Predisposing Factor; Premalignant Cell; Process; Proteins; Recurrence; Reporter; Resolution; Risk; Role; Survival Rate; T cell infiltration; T cell response; T-Lymphocyte; Technology; Testing; Tissue Embedding; Tissue Sample; Tissue imaging; Tissues; Training; Tumor Antigens; Tumor Immunity; United States; United States National Institutes of Health; accurate diagnosis; aggressive therapy; antibody conjugate; cancer invasiveness; clinical translation; cytokine; cytotoxic CD8 T cells; exhaust; follow-up; human data; human tissue; immune cell infiltrate; immunosuppressed; immunosuppressive macrophages; insight; instrumentation; interest; malignant mouth neoplasm; malignant oropharynx neoplasm; mortality; mouth squamous cell carcinoma; multiplexed imaging; neoantigens; neoplastic cell; neutrophil; novel therapeutics; oral cavity epithelium; oral tissue; overexpression; polarized cell; premalignant; prevent; programmed cell death ligand 1; programs; progression risk; risk prediction; risk prediction model; risk stratification; therapeutic development; treatment strategy; tumor; tumor progression; wound healing

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.

项目摘要/摘要 在美国，口服和口咽癌每年导致10,000多人死亡。虽然 局部疾病的口腔鳞状细胞癌（OSCC）患者的存活率高达80％，大约 三分之二在临床上出现与五年生存率相关的区域和遥远转移 和35％。尽管免疫疗法取得了进步，但OSCC的五年死亡率仍然存在 在过去的几十年中，不断不断，强调了早期检测和干预的重要性。 大多数OSCC来自称为口腔上皮异常增生（OED）的癌前病变，仅 其中一些会发展为侵入性癌症。有欧共体会进展的患者可能会从中受益 早期更具侵略性的治疗；但是，与积极治疗相关的病因是 重要的是，阻止他们在所有患者中的广泛使用。尽管这种一般的前景在许多癌症中相似，但 口腔病变的可及性也为详细分析提供了一个独特的机会，以了解 有助于或防止进展为侵入性和恶性癌的生物学过程。 我们将检验以下假设：OED的免疫反应调节进展的风险。 免疫系统应对组织中的破坏和危险。大量证据支持重要的 免疫系统在应对口腔早期病变中的作用，包括丰富的免疫力 细胞渗入这些组织，免疫抑制个体的风险升高以及MHC I类抗原的丧失 许多OSCC肿瘤中的演示机械。但是，免疫反应的功能目前尚未 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）的最新发展使前所未有的详细开发 分析档案病理组织。这项技术，我们最近在一项帮助的帮助下实施了 NIH仪器赠款，使用与重金属记者离子结合的抗体来量化多达50种蛋白质 同时在福尔马林固定石蜡包裹的组织中的亚细胞（400nm）分辨率下。我们已经整理了 来自OED患者的大量临床和后续数据的档案组织，包括 发展为OSCC。在这里，我们将利用MIBI对这些免疫反应进行详细分析 肿瘤，提供有关这些免疫机制和细胞相互作用的新见解 微环境。在AIM 1中，我们将检验以下假设：免疫细胞的类型及其它们的类型 激活状态在进步与没有进步的OED之间是不同的。在AIM 2中，我们 将检验以下假设，即组织内的建筑和细胞邻居在OED中是不同的 这进展到OSCC。在AIM 3中，我们将使用这些数据来识别与和 预测进展风险。这些研究将利用一种新的成像技术来回答基本 有关免疫反应的问题，并指导OED患者的精确治疗决策。