Tumor and immune cell co-evolutionary dynamics as a source of racial disparities in breast cancer

肿瘤和免疫细胞共同进化动力学是乳腺癌种族差异的根源

• 批准号: 10526731
• 负责人: Angela Omilian
• 金额: $ 24.33万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10526731
• 关键词: Address; Affect; African ancestry; Age; Antigen Presentation; Antigens; Bioinformatics; Black Populations; Black race; Blood specimen; Body mass index; Breast Cancer Patient; CD8-Positive T-Lymphocytes; Cell Shape; Cells; Comprehensive Cancer Center; Data; Data Set; Defect; Development; Disease; European; Exclusion; Freezing; Genes; Genetic Variation; Immune; Immune response; Immune system; Immunologic Surveillance; Immunosuppression; Immunotherapy; Infiltration; Lead; Leukocytes; Lymphocyte; Mammary Neoplasms; Methods; Modeling; Molecular Profiling; Mutation; Outcome; Patients; Pattern; Play; Predatory Behavior; Process; Prognosis; Property; Race; Relapse; Research; Resistance; Role; Sampling; Shapes; Source; Techniques; Tissues; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Woman; Work; black patient; black women; cancer health disparity; comparative; design; exhaustion; exome sequencing; immune activation; immunogenicity; improved; malignant breast neoplasm; mortality; mortality risk; neoantigens; neoplastic cell; novel; patient population; personalized medicine; pressure; racial disparity; response; transcriptome sequencing; tumor; tumor growth; tumor microenvironment

ABSTRACT Women of African ancestry (Black women) are more likely to have aggressive breast tumors than White women, and the survival gap between Black and White women is 40%. The tumor immune milieu and its interaction with tumor cells may play a pivotal role in explaining this disparity. African ancestry is associated with a stronger response to immune activation, and breast tumors from Black women have significantly more tumor-infiltrating lymphocytes and CD8+ T cells than White women. Despite this, Black women fare worse than White women with breast cancer, and this at odds with a wealth of studies that show a strong presence of tumor-infiltrating immune cells is correlated with better outcomes. This apparent paradox may be reconciled with Schreiber’s immunoediting model, wherein immune cells interact with the tumor to shape tumor immunogenicity. Because women of African descent have stronger immune responses, we hypothesize that their own immune systems select for more aggressive breast tumors by way of immunoediting. To address this novel hypothesis, we will use frozen breast tumor and blood samples from Roswell Park Comprehensive Cancer Center to obtain a single dataset that will be used to investigate two related research aims. First, we will compare spatial patterns of immune infiltration and genetic diversity within a tumor sample. If immune infiltrates are exerting a selective pressure on tumor cells, spatial regions of high immune infiltration should correspond to lower tumor genetic diversity and these regions are also expected to display molecular signatures of immunoediting, manifested as neoantigen depletion, mutations in antigen presenting genes, immunosuppression, or exclusion. To examine this, tissue cores will be extracted from breast tumors from 80 patients (40 Black, 40 White) – one core from a region of high immune infiltration and one from low infiltration. Whole exome sequencing and RNA-seq will be performed on each tumor core, and sequence data will be examined for genetic diversity and immunoediting using established bioinformatic methods. Second, we will compare breast tumors from Black and White women for immune subsets inferred from RNA-seq data and molecular signatures of immunoediting. We expect that tumors from Black patients will have stronger overall immune responses inferred from RNA-seq data and tumors that show more evidence of immunoediting. Our proposal will employ a suite of bioinformatics techniques to compare the tumor-immune co- evolutionary landscape in breast tumors from Black and White women. Our results may have implications for immunotherapy efficacy by race and may open new avenues for the design of effective combinatory therapies that are personalized for a patient’s immune milieu and/or ancestral background.

摘要 非洲血统的女性(黑人女性)比白人更有可能患有侵袭性乳腺肿瘤 黑人和白人女性之间的存活率差距为40%。肿瘤免疫环境及其影响因素 与肿瘤细胞的相互作用可能在解释这种差异方面发挥关键作用。非洲血统被联系在一起 对免疫激活的反应更强，而来自黑人女性的乳房肿瘤明显更多 肿瘤浸润性淋巴细胞和CD8+T细胞高于白人女性。尽管如此，黑人女性的境况比 患有乳腺癌的白人妇女，这与大量研究表明乳腺癌的强烈存在是不一致的 肿瘤浸润性免疫细胞与更好的预后相关。这一明显的悖论可能会得到调和 在Schreiber的免疫编辑模型中，免疫细胞与肿瘤相互作用形成肿瘤 免疫原性。因为非洲裔女性有更强的免疫反应，我们假设 他们自己的免疫系统通过免疫编辑的方式选择更具侵袭性的乳腺肿瘤。 为了解决这个新的假设，我们将使用冷冻的乳腺肿瘤和罗斯韦尔的血液样本。 PARK综合癌症中心获得一个数据集，该数据集将用于调查两个相关的 研究目的。首先，我们将比较肿瘤内免疫渗透和遗传多样性的空间模式。 样本。如果免疫浸润物正在对肿瘤细胞施加选择性压力，那么高免疫性的空间区域 浸润性应与较低的肿瘤遗传多样性相对应，这些区域也有望显示 免疫编辑的分子特征，表现为新抗原耗尽，抗原呈递突变 基因、免疫抑制或排斥。为了检验这一点，我们将从乳腺肿瘤中提取组织核心。 来自80名患者(40名黑人，40名白人)-一个核心来自高免疫浸润区，一个来自低免疫浸润区 渗透。将对每个肿瘤核心进行整个外显子组测序和rna-seq，并对序列数据进行分析。 将使用已建立的生物信息学方法检查遗传多样性和免疫编辑。第二，我们 将比较黑人和白人妇女的乳腺肿瘤从RNA-SEQ数据中推断的免疫亚群 免疫编辑的分子标记。我们预计黑人患者的肿瘤总体上会更强 从RNA-SEQ数据和显示免疫编辑更多证据的肿瘤中推断出的免疫反应。 我们的计划将使用一套生物信息学技术来比较肿瘤免疫协同作用。 黑人和白人女性乳腺肿瘤的进化图景。我们的结果可能会对 免疫治疗的种族效应，可能为设计有效的联合治疗开辟新的途径 根据患者的免疫环境和/或祖先背景进行个性化设置。