Defining the role of tumoral MHC Class I Expression in Mediating Colorectal Cancer Racial Disparities

定义肿瘤 MHC I 类表达在调节结直肠癌种族差异中的作用

• 批准号: 10737111
• 负责人: Ernest Ramsay Camp
• 金额: $ 64.28万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737111
• 关键词: African American; Agonist; Autologous; Automobile Driving; Biological; Biological Markers; Black Populations; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Etiology; Caucasians; Cellular biology; Cessation of life; Colorectal Cancer; Combination Drug Therapy; Complex; Cytokeratin; Data; Development; Disease; Disparity; Engineering; Engraftment; Exhibits; Flow Cytometry; Fluorouracil; Foundations; Frequencies; Future; Genetic; Goals; Human; Immune; Immune response; Immuno-Chemotherapy; Immunocompetent; Immunologics; Immunologist; Immunotherapy; Incidence; Inflammatory; Interferon Type II; Interleukin-15; Laboratory Finding; MHC Class I Genes; Malignant Neoplasms; Mediating; Mission; Modeling; Mus; National Cancer Institute; Natural Killer Cells; Oncology; Outcome; Patient-Focused Outcomes; Patients; Phenotype; Positioning Attribute; Process; Public Health; Publishing; Race; Research; Research Personnel; Resected; Role; Sampling; Scientist; Secondary to; Solid; Surgeon; Survival Rate; T cell clonality; T cell infiltration; T cell receptor repertoire sequencing; T-Lymphocyte; Testing; Therapeutic; Translating; Tumor Antigens; Tumor Escape; Tumor Immunity; Work; adenoma; anti-PD1 therapy; black patient; cancer health disparity; cancer imaging; cancer infiltrating T cells; chemotherapy; clinical practice; clinically relevant; colon cancer patients; cytokine; design; imaging capabilities; imaging study; immune activation; immune cell infiltrate; improved; mortality; mouse model; multidisciplinary; novel; oxaliplatin; patient derived xenograft model; premalignant; prevent; programmed cell death ligand 1; programs; racial difference; racial disparity; research study; response; spectrograph; synergism; therapeutic evaluation; therapy resistant; treatment response; tumor; tumor progression

PROJECT SUMMARY Compared to Whites, African American/Blacks (AA/B) have a substantially higher (40-50%) colorectal cancer (CRC) mortality rate that is a function of both higher incidence and lower survival rates. Our long-term goal is to understand the differences in immune response that influence this disparity in CRC mortality. Emerging studies suggest alterations in T cell presence and function in AA/B contribute to CRC disparities, and AA/B CRC patients with low immune infiltrate have particularly poor outcomes. We have found that AA/B CRC patients have disproportionally reduced tumoral MHC class I expression compared with White patients. As MHC class I is critical for presentation of tumor antigens to CD8+ T cells, these results suggest a critical immune mediated mechanism that drives the differences in survival times between AA/B and White patients. The objectives of this project are to understand the mechanisms relevant to T cell alterations within the tumors of AA/B versus White patients and to develop improved biomarkers and therapies to reduce CRC racial disparities. Our central hypothesis is that reduced tumoral MHC class I expression drives T cell alterations to enhance tumoral immune escape in CRC from AA/B patients compared with White patients. To test this hypothesis, we have developed robust multispectral imaging capability for studying the relationship between MHC class I expression and CD8+ T cell frequency, localization, phenotype, and function. In parallel, we have developed an autologous humanized CRC TIL-PDX mouse model, created with matched patient-derived tumor and tumor infiltrating T cells (TILs) to investigate CRC disparities. This completely unique approach will be undertaken by a multi-disciplinary team, which includes a surgeon-scientist with expertise in CRC oncology, a cancer immunologist, and a cancer disparities basic researcher. In Aim 1, we will define CD8+ T cell biology in the context of tumoral MHC class I loss in AA/B versus White CRC patients. We will perform both multispectral imaging of archival tumor samples and phenotypical/ functional studies of fresh samples to define essential differences between AA/B and White tumors. In Aim 2, we will evaluate whether TIL-PDX mice generated from AA/B versus White CRC tumors exhibit differential T cell biology and anti-tumor immunity in the context of tumoral MHC class I expression. We expect that the use of the CRC TIL-PDX mouse model will recapitulates a patients’ tumor immunity in a manner not previously possible to determine the differences in immune mediated processes. In Aim 3, we will assess the ability of IL-15 as a therapy to overcome AA/B tumoral MHC class I loss using a syngeneic CRC tumor-bearing mice. The positive impact of this work will be an improved understanding of the differences in immune-mediated mechanisms to understand disparities associated with CRC patient outcomes and to develop a therapeutic approach to help AA/B CRC patients.

项目摘要 与白人相比，非裔美国人/黑人（AA/B）的结直肠癌高（40-50％） （CRC）死亡率是较高事件和较低存活率的函数。我们的长期目标是 了解影响CRC死亡率的这种差异的免疫反应的差异。新兴 研究表明，AA/B中T细胞的存在和功能的改变有助于CRC差异，AA/B CRC 免疫浸润低的患者的预后特别差。我们发现AA/B CRC患者有 与白人患者相比，肿瘤MHC I类表达不成比例降低。作为MHC级我是 对于肿瘤抗原向CD8+ T细胞的呈现至关重要，这些结果表明临界免疫介导 驱动AA/B和白人患者生存时间差异的机制。目标的目标 该项目旨在了解与T细胞改变AA/B肿瘤内的机制 白人患者并开发改进的生物标志物和疗法，以减少CRC种族分布。我们的中心 假设是减少的肿瘤MHC I类表达驱动T细胞改变以增强肿瘤免疫 与白人患者相比，CRC逃脱了AA/B患者。为了检验这一假设，我们已经开发了 强大的多光谱成像能力，用于研究MHC I类表达与CD8+之间的关系 T细胞频率，定位，表型和功能。同时，我们已经开发了一种自体人性化的 CRC TIL-PDX小鼠模型，由匹配的患者衍生肿瘤和肿瘤浸润T细胞（TIL）创建 调查CRC差异。这种完全独特的方法将由多学科团队进行， 其中包括具有CRC肿瘤学专业知识的外科医生科学家，癌症免疫学家和癌症 差异基础研究人员。在AIM 1中，我们将在肿瘤MHC I类中定义CD8+ T细胞生物学 AA/B与白色CRC患者的损失。我们将执行档案肿瘤样品的多光谱成像 以及新鲜样品的表型/功能研究，以定义AA/ B和白色之间的基本差异 肿瘤。在AIM 2中，我们将评估是否是由AA/B产生的TIL-PDX小鼠与白色CRC肿瘤展示的 在肿瘤MHC I类表达的背景下，差异T细胞生物学和抗肿瘤免疫。我们期望 使用CRC TIL-PDX小鼠模型的使用将以某种方式概括患者的肿瘤免疫力 以前可以确定免疫介导过程的差异。在AIM 3中，我们将评估 IL-15作为疗法的能力，可以使用合成性CRC肿瘤克服AA/B肿瘤I类损失 老鼠。这项工作的积极影响将是对免疫介导的差异的改进理解 了解与CRC患者结局相关的分布并发展治疗的机制 帮助AA/B CRC患者的方法。