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，口腔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)患者的局部疾病存活率高达80%，约 三分之二的患者临床上存在区域和远处转移，其五年生存率为50%。 和35%。尽管免疫疗法取得了进展，但口腔鳞癌的五年死亡率仍然保持不变。 在过去的几十年里，这种情况一直不变，强调了及早发现和干预的重要性。 大多数口腔鳞状细胞癌起源于称为口腔上皮异型增生(OED)的癌前病变，仅 其中一些会发展为浸润性癌症。将会进展的OEDs患者可能会受益于 早期更积极的治疗；然而，与积极治疗相关的疾病是 显著，阻止了它们在所有患者中的广泛使用。虽然这一总体前景在许多癌症中都是相似的， 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 促进或防止进展为浸润性癌症和恶性肿瘤的生物过程。 我们将测试对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。重要的证据支持重要的 免疫系统在口腔早期病变反应中的作用，包括丰富的免疫 细胞渗入这些组织，免疫抑制个体的风险增加，MHC-I类抗原丢失 许多口腔鳞癌肿瘤中的呈递机制。然而，免疫反应的特征目前还不是 用于定义治疗策略或对OED或OSCC患者的风险进行分层，呈现未满足的 机会。多路离子束成像(MIBI)的最新发展使得前所未有的详细 档案病理组织分析。这项技术，我们最近在一个 NIH仪器格兰特使用与重金属报告离子结合的抗体对多达50种蛋白质进行定量 同时在福尔马林固定的石蜡包埋组织中以亚细胞(400 Nm)分辨率进行检测。我们已经整理好了 大量来自OED患者的档案组织，以及详细的临床和随访数据，包括 进展到口腔鳞癌。这里，我们将利用MIBI对这些患者的免疫反应进行详细分析 肿瘤，为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 继续进展的OED和没有进展的OED之间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中是不同的假设 后来发展到了OSCC。在目标3中，我们将使用这些数据来识别与和 对进展风险的预测。这些研究将利用一种新的成像技术来回答基本问题 关于免疫反应的问题，并指导OED患者的准确治疗决定。