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

项目摘要 与白人相比，非裔美国人/黑人（AA/B）的结肠直肠癌发病率显著较高（40- 50 (CRC)死亡率是较高发病率和较低存活率的函数。我们的长期目标是 了解免疫反应的差异对CRC死亡率的影响。新兴 研究表明AA/B中T细胞存在和功能的改变有助于CRC差异，AA/B CRC 具有低免疫浸润的患者具有特别差的结果。我们发现AA/B CRC患者 与白色患者相比，肿瘤MHC I类表达明显降低。由于MHC I类是 对于肿瘤抗原呈递给CD 8 + T细胞至关重要，这些结果表明， 导致AA/B和白色患者之间生存时间差异的机制。的目标 本项目旨在了解AA/B肿瘤内T细胞改变的相关机制， 白色患者，并开发改进的生物标志物和治疗方法，以减少CRC种族差异。我们的中央 一种假说认为，肿瘤MHC I类分子表达的降低驱动T细胞改变以增强肿瘤免疫 AA/B患者与白色患者相比，为了验证这一假设，我们开发了 强大的多光谱成像能力，用于研究MHC I类表达与CD 8+之间的关系 T细胞频率、定位、表型和功能。与此同时，我们开发了一种自体人源化 CRC TIL-PDX小鼠模型，用匹配的患者来源的肿瘤和肿瘤浸润性T细胞（TIL）创建， 调查《儿童权利公约》的差异。这一完全独特的方法将由一个多学科小组负责， 其中包括一名具有CRC肿瘤学专业知识的外科医生科学家，一名癌症免疫学家和一名癌症 差距基本研究员。在目标1中，我们将在肿瘤MHC I类的背景下定义CD 8 + T细胞生物学。 AA/B与白色CRC患者的损失。我们将对存档的肿瘤样本进行多光谱成像， 新鲜样本的表型/功能研究，以确定AA/B和白色之间的本质差异 肿瘤的在目标2中，我们将评估由AA/B与白色CRC肿瘤产生的TIL-PDX小鼠是否表现出与对照组相比的肿瘤生长抑制。 在肿瘤MHC I类表达的背景下的差异T细胞生物学和抗肿瘤免疫。我们预计 CRC TIL-PDX小鼠模型的使用将以一种方式重现患者的肿瘤免疫， 以前可能确定免疫介导过程的差异。在目标3中，我们将评估 IL-15作为一种疗法克服AA/B肿瘤MHC I类缺失的能力， 小鼠这项工作的积极影响将是更好地理解免疫介导的 了解与CRC患者结局相关的差异并开发治疗方案的机制 方法来帮助AA/B CRC患者。

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.