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显著更高 转移。癌症发病率和患者预后的这种差异不能仅仅是 由文化和社会经济因素解释，有必要确定 控制这些差异的分子机制。临床前和临床研究已经 发现肿瘤微环境(TME)组成和结构的差异 在乳腺癌患者中与黑人患者截然不同。微血管密度、巨噬细胞 已经证明在Black中存在免疫相关基因的渗透和上调 女性与白人女性的对比支持种族差异可能有助于 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生和发展部分是由种族因素引起的 肿瘤-免疫相互作用的差异。这项提案将审查空间如何 TME的架构反映了不同的肿瘤-免疫相互作用，以及这些 相互作用启动了播散性肿瘤细胞的全身免疫耐受，使 特定于大脑的转移瘤。 斯坦福大学病理学和神经病理学系构建了一种组织 包含来自不同组的脑转移瘤和原发肿瘤的微阵列(TMA) 乳腺癌患者的比例。我们将描述这些TMA的空间结构 使用多路传输离子束成像(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的多达39种蛋白质- 嵌入组织样本以在亚细胞上创建高维肿瘤免疫图谱 决议。利用MIBI，我们将构建两者的原位亚细胞蛋白质空间图谱 原发性乳腺癌和乳腺癌脑转移TME。我们随后将 鉴别原发灶和脑转移瘤的不同特征 在黑人女性和其他种族群体之间表达。我们将专注于识别 肿瘤免疫微环境的特征(免疫成分、空间分布 架构、肿瘤免疫相互作用)，根据患者种族的不同而不同。结果来自于 该项目将有助于制定适当的预测和目标 针对患有乳腺癌的黑人女性的治疗。

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.