UBC Theses and Dissertations
The effects of mammary tumours on hematopoiesis and dendritic cell development Sio, Alexander
Tumours are often associated with defects in hematopoiesis and DC function. Leukocytosis, anemia, development of immunosuppressive cells such as MDSCs and tolerogenic DCs are all part of tumour development. In breast cancer, although these hematopoietic and DC defects may serve as prognostic indicators, little is known about their origin. Our studies show that mammary tumours affect the hematopoietic system leading to myeloproliferative-like disease characterized by neutrophilia, anemia, and defects in the HSPC compartment. These defects were associated with changes in global epigenetic regulation, and specifically in the upregulation and histone methylation status of Hoxa genes, most notably Hoxa9, a gene that critically controls HSPC differentiation. These changes in gene regulation and HSPC defects were found to be driven by tumour-secreted G-CSF. Additionally, our research shows that the generation of immunosuppressive DCs in mammary tumour bearing mice was associated with impaired DC differentiation, where DCs that develop in the presence of mammary tumours and their factors acquire immunosuppressive features. G-CSF played an important role in the suppression of DC development. Tumour derived factors induced FLT3L and GMCSF DCs to expression Arginase-I, an enzyme known to suppress T cell proliferation and induce tolerance. Our data revealed the expression of Arg1 in these DCs was associated with enabling histone modifications in the Arg1 locus. Targeting of G-CSF may alleviate tumourinduced symptoms of anemia, leukocytosis, and DC defects, resulting in better patient survival and preventing DC immunosuppression.
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