Inflammatory Cells and Mediators in the Tumor Microenvironment of Breast Cancer

Breast cancer is the most common cancer type among women. There are different subtypes of breast cancer, all with different prognosis. They are defined by their receptor status of Estrogen-, Progesterone-, and HER2receptor expression (ER, PR, HER2). The most aggressive subtype is the Triple Negative (ER-PR-HER2-; TNBC) subtype. The tumor microenvironment also consists of non-malignant cells of various origin. Immune cells infiltrate tumors as a natural host protective reaction. Various immune cells infiltrate breast tumors depending on the breast cancer subtype. In this thesis, the interplay between immune cells, breast cancer cells and other non-malignant cells in the tumor microenvironment are investigated. In the first part of the thesis, we showed that the innate immune receptor, toll-like receptor 4 (TLR4), was expressed on the malignant cells of ER-PRbreast cancers. TLR4-expression correlated to a negative clinical prognosis in breast cancer patients. We also showed that the expressed TLR4 is functional since it responds to ligands belonging the dangerand pathogen associated molecular pattern families (DAMP and PAMP). In the second part of this thesis we show that the DAMP and TLR4 ligand, S100A9, was expressed by both malignant cells in ER-PRbreast cancer subtype and by infiltrating CD163+ myeloid cells. Moreover, S100A9 expression in myeloid cells correlated with decreased overall survival in breast cancer patients. In the third part of this thesis, we investigated the interplay of primary human myeloid cells and breast cancer cells in vivo. We performed a co-transplantation model of primary human monocytes from healthy donors with either luminal A or TNBC breast cancer cell lines in immunodeficient NSG mice. We observed that the human monocytes survived, proliferated and differentiated into anti-inflammatory CD163+ myeloid cells in TNBCs in these mice. The transplanted monocytes promoted stroma formation in both tumor types, but were able to activate fibroblasts in the TNBC microenvironment only. This indicates that monocytes may influence tumor progression differently in distinct breast cancer subtypes. This finding could be of importance for the targeted therapy against myeloid cells in the treatment of breast cancer. Finally, using immunohistochemistry on a large breast cancer cohort, we investigated the impact of different tumor infiltrating T cell subtypes with the aim to understand whether they differ between breast tumor subtypes. Using selected T cell subset markers against; CD3+ T cells, CD8α+ T cells, γδ T cells, FoxP3+ T cells (Treg) and IL-17+ T cells, we observed different prognostic outcomes in various breast cancer subtypes. Infiltration of γδ T cells was associated with a better clinical outcome in all breast cancer subtype except the TNBC subtype, while the opposite was observed for Tregs. However, infiltration of CD3+ T cells and CD8α + T cells was independently associated with an improved prognosis for all breast cancer patients. The results indicate that different T cell subtypes have different functions and outcome depending on the breast cancer subtype. In conclusion, this thesis investigates the role of inflammatory cells and mediators in breast cancer progression. The findings from this thesis could contribute to the understanding of which breast cancer subtypes that will profit from novel therapies against specific immune cell populations and mediators.