Do Tumor-Immune Interactions Prime Systemic Tolerance of Triple-Negative Breast Cancer Brain Metastases?

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PROJECT ABSTRACT/SUMMARY It is widely estimated that 90% of cancer-related deaths are caused by metastasis. This statistic underscores our inability to manage cancer once it disseminates through the body, and our need to better understand the molecular mechanisms that drive metastasis. Triple-negative breast cancer (TNBC) is a subtype of breast cancer that occurs in 10-20% of cases. Taken as a group, TNBCs pose an unmet clinical challenge in many ways: (1) TNBCs represents the most aggressive and most metastatic subtype of breast cancer, (2) up to 46% of late-stage TNBC patients will develop brain metastases, (3) TNBC patients are at four-times higher risk of developing diffuse metastases on the surface of the brain (leptomeningeal disease), which is rapidly and universally fatal, and 4) women of African ancestry have an up to 80% higher likelihood of developing TNBC – making TNBC a cancer disparity. Previous studies demonstrate that primary TNBC is highly immunogenic, and immune infiltration is associated with improved prognosis. However, little is known about the immune environment in TNBC brain metastases and how tumor-immune interactions effect metastatic potential. Recognizing these pressing issues, I have chosen to focus my career as an independent cancer researcher on using a systems biology approach to uncover molecular mechanisms that underlie metastasis and race- specific cancer disparities. A comprehensive mentoring, research, and career development plan will be executed over the course of the K99 and R00 training period, which will provide me with the necessary tools to make an early transition to independence. First, to visualize tumor-immune interactions, I will construct an in-situ protein map of TNBC brain metastases using MIBI – a cutting-edge multiplexed imaging method (AIM 1). I will use a validated imaging analysis pipeline to quantitate the composition and spatial architecture of the tumor-immune microenvironment and determine the extent to which these features correlate with patient outcomes. In AIM 2, I will identify tumor-immune receptor-ligand pairs using single-cell RNA-sequencing on TNBC brain metastases samples. Lastly, in AIM 3, I will use MIBI to visualize tumor-immune interactions in primary TNBCs to determine whether interactions in the primary tumor microenvironment prime immune system tolerance of disseminated tumor cells enabling brain metastases. I will validate relevant targets by measuring their expression in patient cerebral spinal fluid (CSF), which contains brain-tumor- associated cell-free RNA. The results of my proposed postdoctoral research will positively impact public health as they will reveal key tumor-immune interactions responsible for priming the immune system for metastasis, and will generate the first “TNBC brain metastasis interactome”. My results will lead to the discovery of new molecular targets with the primary goal of reducing metastasis-driven cancer mortality. The K99 career development plan and focused research training will be critical to expand my skillset in biocomputation – a necessary component of my proposed research; as well as fill any gaps in my background, preparing me for a timely and successful transition to the R00 independent phase. Overall, the dual-phase award will significantly enhance my research, and ensure my continued contribution to public health and increasing diversity in science, as an established cancer researcher.