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

黑人女性从乳房到大脑的发病率和死亡率明显较高 转移癌症发病率和患者结局的这种差异不能仅仅是 文化和社会经济因素的解释，需要确定 控制这些差异的分子机制。临床前和临床研究 发现肿瘤微环境（TME）组成和结构的差异 这在乳腺癌患者和黑人患者中是不同的。微血管密度，巨噬细胞 浸润和免疫相关基因的上调已被证明存在于黑色 与白色女性相比， TME的明显变化。目前对乳腺癌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 黑人女性乳腺癌的发病率和进展部分是由于种族原因， 肿瘤免疫相互作用的差异。该提案将研究空间 TME的结构反映了不同的肿瘤-免疫相互作用，以及这些相互作用是如何发生的。 相互作用引发了播散性肿瘤细胞的全身免疫耐受， 脑转移 斯坦福大学的病理学和神经病理学部门已经构建了一个组织 包含来自不同组的脑转移瘤和原发性肿瘤的微阵列（TMA） 乳腺癌患者。我们将描述这些TMA的空间结构 使用多路复用离子束成像（MIBI）。MIBI是一项尖端技术， 能够同时定量福尔马林固定的石蜡中多达39种蛋白质， 包埋的组织样本，以在亚细胞水平上创建高维肿瘤免疫图， 分辨率使用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 确定原发性和脑转移瘤TME的差异特征， 黑人妇女和其他种族群体之间的关系。我们将集中精力识别 肿瘤免疫微环境的特征（免疫组成、空间分布、免疫功能） 结构、肿瘤-免疫相互作用），其基于患者种族而变化。的结果 该项目将有助于制定适当的说明和有针对性的 治疗患有乳腺癌的黑人女性。

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.