Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer.

Jai Rautela,Andreas Möller,Bradley N Bidwell,Belinda S Parker,Nikola Baschuk,Peter Lock,Kun Xiao,Daniel M Andrews,Robin L Anderson,Edwin D Hawkins,Erin C Lucas,Clare Y Slaney,Christina S Wong,Krishnath M Jayatilleke,Paul J Hertzog,Weisan Chen

doi:10.1158/2326-6066.cir-15-0065

Abstract

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.

Highlights

Metastasis is the deadliest result of malignant disease
We studied the full course of disease in a model of spontaneous breast tumorigenesis (MMTV-PyMT) as well as in two orthotopic models (4T1 & 66cl4) of breast cancer metastasis in wild-type (WT) and Ifnar1À/À mice
We have demonstrated that three non-bone metastatic breast tumor models can successfully colonize the bone in hosts with a defective type-I IFN pathway—underscoring the importance of IFN signaling during the antimetastatic response

Summary

Introduction

Metastasis is the deadliest result of malignant disease. Standard clinical practice to avoid this outcome focuses on primary tumor treatment using chemotherapy, radiotherapy, and/or surgical resection. Metastatic cascade has uncovered numerous mechanisms of disseminated tumor cell survival and outgrowth, such as resisting apoptosis following detachment from the extracellular matrix [2], de-novo angiogenesis [3], and growth factor signaling pathways that promote the proliferation of disseminated cells [4]. The type-I IFN family was originally characterized as a group of soluble factors produced by almost all cells in the body that were able to confer an antiviral state [8, 9] Our knowledge of these cytokines has since broadened to include their ability to directly inhibit the proliferation of various malignant cells and to induce antitumor immune responses [10, 11]. This work shows a critical role for type-I IFN signaling in promoting the antimetastatic response and highlights the importance of examining the full course of disease when investigating tumor immunity

Materials and Methods

Results and Discussion

Concluding Remarks

Disclosure of Potential Conflicts of Interest