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Mammary tumour-induced dysregulation in hematopoiesis and DC development and the role of Lyn tyrosine kinase in DC activation

University of British Columbia

Previous studies have revealed that perturbations in myelopoiesis can lead to the emergence of immature cells, which can facilitate tumorigenesis and metastasis. Our studies showed that mammary tumours led to a myeloproliferative-like disease, characterized by anemia, leukocytosis, expansion of immature myeloid cells, and defects in the hematopoietic stem and progenitor cell (HSPC) compartment in tumour-bearing mice. Furthermore, mammary tumours impaired DC development resulting in the accumulation of DC progenitors and the emergence of immunosuppressive DCs with impaired ability to activate NK and T cells. Mammary tumour-bearing mice exhibited a shift in hematopoiesis from the bone marrow to the spleen, with large numbers of primitive and committed progenitors accumulating in the spleen. Mammary tumour development was also associated with epigenetic modifications that facilitated the expression of key hematopoiesis and leukemia regulatory genes, such as Hoxa9, a gene that critically controls HSPC differentiation. Using in vitro assays, we identified mammary tumour derived G-CSF as the factor mediating the dysregulation of the HSPC compartment and suppressing DC development. DCs are critical for the priming/activation of NK cells and cytotoxic T lymphocytes, which together are critical components of the anti-tumour immune response. Therefore, proper regulation of signaling thresholds is critical for DC activation and function. Lyn tyrosine kinase is important in regulating signaling thresholds in immune cells, including DCs, and Lyn gain-of-function (Lynup/up) mice show increased sensitivity to PAMPs (i.e. LPS) characterized by high levels of proinflammatory cytokines and increased susceptibility to endotoxin-mediated death. Our studies demonstrated that DCs were necessary for the enhanced LPS-induced inflammation in Lynup/up mice, by priming excessive IFN-γ production by NK cells. As such, we hypothesized that enhanced Lyn activity, and the associated changes in DC development and activation will evoke improved anti-tumour immune responses and preliminary data from our lab demonstrates that Lynup/up mice develop smaller mammary tumours than wild type mice. Taken together, our results suggest that targeting mammary tumour derived G-CSF may reverse mammary tumour-induced anemia, leukocytosis, and DC defects, conversely enhancing DC function by increasing Lyn activity may result in in a more robust anti-tumour immune response, leading to increased survival of breast cancer patients.

Text

2014-09-10

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/50336

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/