Journal
CANCER IMMUNOLOGY RESEARCH
Volume 3, Issue 11, Pages 1207-1217Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-15-0065
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Funding
- Cancer Council Victoria
- National Health and Medical Research Council (NHMRC)
- NHMRC
- ARC
- National Breast Cancer Foundation [NBCF]
- Cure Cancer Australia
- National Breast Cancer Foundation [NC-13-26, CG-10-04, PS-15-022, PF-12-14] Funding Source: researchfish
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Metastatic progression is the major cause of breast cancer-related mortality. By examining multiple syngeneic preclinical breast cancer models in mice lacking a functional type-I interferon receptor (Ifnar1(-/-) mice), we show that host-derived type-I interferon (IFN) signaling is a critical determinant of metastatic spread that is independent of primary tumor growth. In particular, we show that bone metastasis can be accelerated in Balb/c Ifnar1(-/-) mice bearing either 4T1 or 66cl4 orthotopic tumors and, for the first time, present data showing the development of bone metastasis in the C57Bl/6 spontaneous MMTV-PyMT-driven model of tumorigenesis. Further exploration of these results revealed that endogenous type-I IFN signaling to the host hematopoietic system is a key determinant of metastasis-free survival and critical to the responsiveness of the circulating natural killer (NK)-cell population. We find that in vivo-stimulated NK cells derived from wild-type, but not Ifnar1(-/-), mice can eliminate the 4T1 and 66cl4 breast tumor lines with varying kinetics in vitro. Together, this study indicates that the dysregulated immunity resulting from a loss of host type-I IFN signaling is sufficient to drive metastasis, and provides a rationale for targeting the endogenous type-I IFN pathway as an antimetastatic strategy. (C) 2015 AACR.
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