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

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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.