Function of Innate Immune Cells in Breast Cancer

Sammanfattning: Tumor associated macrophages (TAMs) are key cells in creating an immunosuppressive tumor microenvironment (TME). In general, presence of TAMs is associated with worse outcome in cancer patients. Macrophages with anti-tumor effect can be found in the TME but are usually in minority. This thesis focuses on the role of innate immune cells, and especially macrophages, in breast cancer. In the first project we showed that pro-inflammatory macrophages downregulate estrogen receptor alpha (ERα) on breast cancer cells. We unveiled the molecular mechanism behind this, showing that TNF-α derived from macrophages inactivates transcription factor FOXO3a. Moreover, presence of TAMs in breast cancer tumors associated with ER negativity and worse prognosis in ERα+ patients. In projects two and three we shifted our focus towards CD169+ macrophages in lymph nodes (LN) and primary tumors (PT) of breast cancer patients. In project II we showed that presence of CD169+ macrophages in metastatic LN correlated with better prognosis, while presence of CD169+ macrophages in PT did not. Association with PD-L1 expression was found in both locations. In project III we saw that CD169+ TAMs are most likely monocyte derived in a type I IFN environment and display a unique pro-inflammatory phenotype and cytokine profile, but with immunosuppressive function. In a patient cohort they were associated with tertiary lymphoid structures and regulatory T cells, and therefore with worse prognosis.In conclusion, TAMs represent a broad spectrum of macrophages with unique origin, phenotype, and function. In this thesis we have added to the growing knowledge of these cells and their role in breast cancer. Not only does the type of cancer matter for their function, but further their location and surrounding environment within breast cancer.