Immunosuppressive Myeloid Cells in Breast Cancer and Sepsis
Author
Summary, in English
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.
Department/s
- Department of Translational Medicine
- Cancer Immunology, Malmö
- Experimental Infection Medicine, Malmö
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publishing year
2014
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2014:23
Full text
- Available as PDF - 21 MB
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Document type
Dissertation
Publisher
Department of Laboratory Medicine, Lund University
Topic
- Clinical Medicine
Status
Published
Research group
- Cancer Immunology, Malmö
- Experimental Infection Medicine, Malmö
Supervisor
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-87651-47-2
Defence date
7 March 2014
Defence time
09:15
Defence place
The main lecture hall, Pathology building, Skåne University Hospital Malmö
Opponent
- Ida Stenfeldt Mathiasen