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: 10791951
• 负责人: Matthew Spitzer
• 金额: $ 13.6万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10791951
• 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.

项目概要/摘要 在美国，口腔癌和口咽癌每年导致 10,000 多人死亡。虽然 局部病变的口腔鳞状细胞癌 (OSCC) 患者的生存率高达 80%，约为 三分之二的患者临床上存在区域和远处转移，五年生存率为 50% 和35%，分别。尽管免疫治疗取得了进展，但口腔鳞状细胞癌的五年死亡率仍然很高 过去几十年来一直如此，凸显了早期发现和干预的重要性。 大多数 OSCC 源自称为口腔上皮发育不良 (OED) 的癌前病变，仅 其中一些将进展为侵袭性癌症。 OED 进展的患者可能会受益于 尽早采取更积极的治疗；然而，与积极治疗相关的发病率是 显着，阻碍了它们在所有患者中的广泛使用。虽然许多癌症的总体前景相似， 口腔病变的可及性也为详细分析以了解口腔病变提供了独特的机会 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《牛津英语词典》的免疫反应调节进展风险的假设。 免疫系统对组织的破坏和危险做出反应。重要的证据支持重要的 免疫系统在应对口腔早期病变中的作用，包括丰富的免疫细胞 细胞浸润这些组织，免疫抑制个体的风险增加，并且 MHC I 类抗原丢失 许多 OSCC 肿瘤中的表现机制。然而，免疫反应的特征目前尚不明确。 用于定义治疗策略或对 OED 或 OSCC 患者的风险进行分层，提出未满足的要求 机会。多重离子束成像 (MIBI) 的最新发展使得前所未有的详细 档案病理组织分析。我们最近在一家公司的帮助下实施了这项技术 NIH 仪器补助金，使用与重金属报告离子缀合的抗体来定量多达 50 种蛋白质 在福尔马林固定石蜡包埋的组织中同时以亚细胞（400nm）分辨率进行检测。我们整理了 来自 OED 患者的大量档案组织，包含详细的临床和随访数据，包括 进展为 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，为这些肿瘤中的免疫机制和细胞相互作用提供了新的见解 微环境。在目标 1 中，我们将检验以下假设：存在的免疫细胞类型及其作用 继续进展的牛津英语词典与未进展的牛津英语词典的激活状态是不同的。在目标 2 中，我们 将检验组织内的结构和细胞邻域在 OED 中不同的假设 进展到 OSCC。在目标 3 中，我们将使用这些数据来识别与以下相关的免疫特征： 预测进展风险。这些研究将利用新的成像技术来回答基本问题 有关免疫反应的问题并指导 OED 患者的精确治疗决策。