Immunosuppressive Myeloid Cells in Breast Cancer and Sepsis

Sammanfattning: Immune cells play paradoxical roles in cancer progression. On one hand, the immune system protects us against tumor development by recognizing and eliminating cancerous cells. On the other hand, tumor-associated immune cells can contribute to tumor progression by secreting growth factors as well as immunosuppressive, pro-angiogenic and/or pro-metastatic mediators.
In this thesis we identified a factor (Wnt5a) that may be involved in skewing immune responses towards immunosuppressive, tumor promoting immune cell populations. In a pro-inflammatory setting (i.e. in the presence of exogenous pathogen-associated molecular patterns; PAMPs, or endogenous damage-associated molecular patterns; DAMPs), Wnt5a promoted the generation of immunosuppressive monocytes (CD14+HLA-DRlow/-Co-receptorlow/-). This was at the expense of generation of pro-inflammatory macrophages (M1). In addition, Wnt5a inhibited monocyte to dendritic cell differentiation (Mo-mDC). When co-injecting monocytes from healthy blood donors with MCF-7 or MDA-MB-231 breast cancer cells (luminal A and basal-like, respectively) into immunodeficient mice, monocytes promoted the generation of an activated tumor stroma and were preferentially recruited to basal-like tumors. Furthermore, monocytes from breast cancer patients were affected early during the disease, gradually becoming reprogrammed towards a novel population of monocytic myeloid-derived suppressor cells (Mo-MDSCs). The gene-expression profile of cancer-derived monocytes was remarkably similar to that of reprogrammed immunosuppressive monocytes from patients with gram-negative sepsis. This suggests that Mo-MDSCs may be generated in a similar manner in cancer and sepsis (by reprogramming of monocytes towards an immunosuppressive phenotype). We finally propose that Mo-MDSCs and granulocytic MDSCs are preferentially induced by different PAMPs.
Altogether, we conclude that myeloid cells are skewed towards an immunosuppressive and tissue remodeling phenotype early during breast cancer. This resembles the situation during severe infections such as sepsis and most likely has a positive impact on tumor progression.