Deconvolution and interruption of the cancer-neuro-immune axis facilitating brain metastases

癌症-神经-免疫轴的反卷积和中断促进脑转移

基本信息

批准号：
10747824
负责人：
Melanie Hayden Gephart
金额：
$ 7.64万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10747824
关键词：
Architecture Brain Breast Breast Cancer Patient Clinical Research Environment Ethnic Origin Exhibits Formalin Genes Immune Immune Tolerance In Situ Incidence Infiltration Interruption Macrophage Malignant Neoplasms Maps Metastatic malignant neoplasm to brain Molecular Multiplexed Ion Beam Imaging Neoplasm Metastasis Neuroimmune Paraffin Embedding Pathology Patient-Focused Outcomes Patients Primary Neoplasm Proteins Race Resolution Socioeconomic Factors Technology Tissue Microarray Tissue Sample Up-Regulation Variant Woman black patient black women breast cancer progression density differential expression high dimensionality immunoregulation malignant breast neoplasm mortality neoplastic cell neuropathology preclinical study prognostication racial population targeted treatment tumor tumor microenvironment tumor-immune system interactions

项目摘要

Black women exhibit a significantly higher incidence and mortality from breast-to-brain metastasis. This difference in cancer incidence and patient outcomes cannot be solely explained by cultural and socioeconomic factors necessitating the need to identify molecular mechanisms governing these differences. Preclinical and clinical studies have discovered differences in tumor microenvironment (TME) composition and architecture that are distinct in breast cancers from Black patients. Microvessel density, macrophage infiltration, and upregulation of immune-related genes have been shown to exist in Black women compared to White women supporting the idea that ethnic variation can contribute to distinct changes in the TME. Little is known about the immune environment in breast cancer brain metastases especially in Black patients. We hypothesize that increased incidence and progression of breast cancer in Black women is in part due to race-based differences in tumor-immune interactions. This proposal will examine how the spatial architecture of the TME reflects distinct tumor-immune interactions, and how these interactions prime systemic immune tolerance of disseminated tumor cells, enabling brain-specific metastases. Stanford Pathology and Neuropathology departments have constructed a tissue microarray (TMA) containing brain metastases and primary tumors from a diverse group of breast cancer patients. We will characterize the spatial architecture of these TMAs using multiplexed ion beam imaging (MIBI). MIBI is a cutting -edge technology that enables simultaneous quantification of up to 39 proteins in formalin-fixed, paraffin- embedded tissue samples to create high dimensional tumor-immune maps at subcellular resolution. Using MIBI, we will construct in-situ subcellular protein spatial maps of both primary breast cancer and breast cancer brain metastases TME. We will subsequently identify features of the primary and brain metastases TMEs that are differentially expressed between Black women and other racial groups. We will focus on identifying features of the tumor-immune microenvironment (immune composition, spatial architecture, tumor-immune interactions) that vary based on patient race. The results from this project will be instrumental in developing appropriate prognostication and targeted therapies for Black women with breast cancer.

黑人女性从乳房到大脑的发病率和死亡率明显更高转移。癌症发病率和患者结果的这种差异不能仅仅归因于由文化和社会经济因素解释，需要确定控制这些差异的分子机制。临床前和临床研究已发现肿瘤微环境（TME）组成和结构的差异这与黑人患者的乳腺癌不同。微血管密度、巨噬细胞已证明黑人中存在免疫相关基因的渗透和上调女性与白人女性相比支持种族差异可以促进这一观点 TME 的明显变化。对乳房的免疫环境知之甚少癌症脑转移，尤其是黑人患者。我们假设增加了黑人女性乳腺癌的发病率和进展部分归因于种族因素肿瘤与免疫相互作用的差异。该提案将研究空间如何 TME 的结构反映了不同的肿瘤-免疫相互作用，以及这些相互作用如何相互作用引发播散性肿瘤细胞的系统免疫耐受，从而使脑特异性转移。斯坦福病理学和神经病理学部门构建了一个组织包含来自不同组的脑转移瘤和原发肿瘤的微阵列（TMA）的乳腺癌患者。我们将描述这些 TMA 的空间架构使用多重离子束成像（MIBI）。 MIBI是一项尖端技术，能够同时定量福尔马林固定、石蜡中多达 39 种蛋白质嵌入组织样本以在亚细胞处创建高维肿瘤免疫图解决。使用 MIBI，我们将构建两者的原位亚细胞蛋白质空间图原发性乳腺癌和乳腺癌脑转移 TME。我们随后将识别原发 TME 和脑转移 TME 的不同特征在黑人妇女和其他种族群体之间表达。我们将重点识别肿瘤免疫微环境的特征（免疫组成、空间结构、肿瘤-免疫相互作用）根据患者种族而变化。结果来自该项目将有助于制定适当的预测和有针对性的患有乳腺癌的黑人女性的治疗方法。