Immune and transcriptomic biomarkers of progressive oral premalignant lesions

进行性口腔癌前病变的免疫和转录组生物标志物

• 批准号: 10770711
• 负责人: Fatemeh Momen Heravi
• 金额: $ 74.31万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10770711
• 关键词: Address; Alcohols; Biological Markers; CD8-Positive T-Lymphocytes; Cancer Etiology; Cells; Cessation of life; Characteristics; Clinical; Code; Communities; Data; Data Set; Development; Diagnosis; Disease; Early Diagnosis; Early identification; Etiology; Fluorescence; Gene Combinations; Gene Expression; HPV-High Risk; Heterogeneity; Histologic; Histopathologic Grade; Human Papillomavirus; Immune; Immunologic Markers; Immunotherapy; Incidence; Individual; Knowledge; Lesion; Leukoplakia; Machine Learning; Malignant - descriptor; Malignant Conversion; Malignant Neoplasms; Microscopic; Modality; Modeling; Molecular; Morbidity - disease rate; NCI-Designated Cancer Center; Oral; Oral Examination; Oral Leukoplakia; Oral Stage; Patients; Persons; Play; Population Heterogeneity; Prevention; Risk; Risk Assessment; Role; Specimen; Survival Rate; Tissues; Tobacco; Transcript; Translations; Tumor-associated macrophages; Universities; Untranslated RNA; Validation; biobank; biomarker identification; clinical biomarkers; clinical decision-making; cohort; conventional therapy; follow-up; high risk; improved; malignant mouth neoplasm; malignant oropharynx neoplasm; mortality; mouth squamous cell carcinoma; multidisciplinary; neoplastic; oral lesion; premalignant; progression marker; progression risk; racial diversity; recruit; response; risk prediction model; risk stratification; screening; survival outcome; transcriptome sequencing; transcriptomics; tumor; tumor-immune system interactions

PROJECT SUMMARY Oral squamous cell carcinoma (OSCC) is the 6th leading cause of cancer-related mortality worldwide. OSCC is curable with favorable survival outcomes if detected early. The majority of OSCCs are preceded by oral potentially malignant disorders (OPMDs) with oral leukoplakia or white lesions being the most common type. However, not all oral leukoplakia progresses to OSCC. Accurate identification of OPMDs that are likely to progress to OSCC offers the best strategy for OSCC prevention and management and can lead to decreasing patients’ morbidity and mortality through earlier detection. Although proven inadequate, microscopic examination and histological grading remain the gold standard for predication of malignant transformation. For instance, some low-grade OPMDs will progress to OSCC but not all high-grade OPMDs progress to OSCC. There is an urgent and unmet demand for highly efficacious biomarkers to identify progressive leukoplakias with a high risk of OSCC conversion. Addressing this knowledge gap can lead to early detection of HPV-negative OSCC and improve patient survival. Examining OPMDs with and without malignant transformation, we have found specific transcriptomic signatures which are associated with progressive OPMDs. Using spatial transcriptomics and multiplex immune fluorescence (mIF), we observed that malignantly transformed OPMDs have significantly increased immunosuppressive tumor-associated macrophages (enriched in ARG1) and low levels of CD8+ T- cells. Our central hypothesis is that the levels and trajectories of such signatures in tissues are predictive of the malignant conversion of OPMDs to OSCC. The primary objective of this multi-disciplinary U01 collaborative study is to identify and validate transcriptomic and immune signatures that can discriminate OPMDs predicted to malignantly progress and develop, validate, and refine a risk stratification model based on identified biomarkers and clinical variables. In Aims 1 and 2, we will leverage a well-characterized, racially diverse population of over 500 individuals with histologically confirmed OPMDs. We will validate our list of transcriptomic and immune-related biomarkers and perform RNA sequencing and spatial transcriptomics to identify potential additional transcripts associated with the malignant progression of OPMDs. In Aim 3, we will develop a combination risk score formula based on selected transcriptomics and immune biomarkers and clinicodemographic variables to predict OMPD malignant progression based on our internal cohort. We will validate the combination risk score formula in an independent cohort of 300 patients. The risk score formula can be used by clinicians for risk assessment and clinical decision making. The contribution from this project is expected to be significant as it can lead to introduction of a personalized risk stratification approach for management of OPMDs. Detecting preneoplastic lesions with high malignant transformation risk will substantially increase patient survival while maximizing OSCC screening benefits.

项目摘要 口腔鳞状细胞癌（OSCC）是全球第六大癌症相关死亡原因。OSCC是 如果早期发现，可以治愈并有良好的生存结局。大多数OSCC之前都是口头的 潜在恶性疾病（OPMD），其中口腔白斑或白色病变是最常见的类型。 然而，并不是所有的口腔白斑都会发展为OSCC。准确识别可能 OSCC的进展为OSCC的预防和管理提供了最佳策略， 通过早期发现降低患者的发病率和死亡率。虽然被证明是不充分的，显微镜检查 组织学分级仍然是预测恶性转化的金标准。例如有些 低级别的OPMD将发展为OSCC，但不是所有的高级别OPMD都发展为OSCC。目前迫切 以及对高度有效的生物标志物的未满足的需求，以识别具有高OSCC风险的进行性白斑 转换.解决这一知识缺口可以导致HPV阴性口腔鳞状细胞癌的早期发现， 患者生存率。检查有和没有恶性转化的OPMD，我们发现了特异性的 与进行性OPMD相关的转录组学签名。使用空间转录组学， 多重免疫荧光（mIF），我们观察到恶性转化的OPMD具有显著的 增加的免疫抑制性肿瘤相关巨噬细胞（富含ARG1）和低水平的CD8 + T- 细胞我们的中心假设是，组织中这些特征的水平和轨迹可以预测组织中的细胞凋亡。 OPMD向OSCC的恶性转化。这个多学科U01合作的主要目标 这项研究旨在鉴定和验证可以区分预测的OPMD的转录组学和免疫特征， 恶意地发展和开发，验证和完善基于已识别的风险分层模型 生物标志物和临床变量。在目标1和2中，我们将利用一个特征鲜明、种族多样的 超过500例经组织学证实的OPMD患者。我们将验证我们的转录组列表 和免疫相关的生物标志物，并进行RNA测序和空间转录组学，以确定潜在的 与OPMD恶性进展相关的其他转录物。在目标3中，我们将开发一个 基于选定的转录组学和免疫生物标志物的组合风险评分公式， 临床人口统计学变量预测OMPD恶性进展。我们将 在300名患者的独立队列中验证组合风险评分公式。风险评分公式可以 供临床医生用于风险评估和临床决策。该项目的贡献是 预计将是重要的，因为它可以导致引入个性化的风险分层方法， OPMD的管理。检测具有高恶性转化风险的癌前病变将基本上 提高患者生存率，同时最大限度地提高OSCC筛查的益处。