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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.

黑人妇女从乳房到脑部的发病率和死亡率明显更高