Abstract 1545: Education of macrophages through modulation of NF-kappaB: an opportunity for targeted therapy.

Abstract

Abstract Macrophages are a plastic cell type, capable of adapting to numerous signals within their environment. As part of the innate immune system, macrophages were traditionally considered anti-tumor (M1), but it has been well established that macrophages can also help to create a pro-tumor, pro-metastatic tumor niche (M2). NF-κB transcription factors can regulate both pro- (MMP's, VEGF) and anti-tumor (iNOS) downstream targets within macrophages, suggesting that modulation of NF-κB may play a role in the two different macrophage phenotypes. However, our understanding of NF-κB signaling specifically within macrophages during tumor progression is limited. To this end, we have developed murine transgenic models that enable us to induce expression of an activator or dominant inhibitor of NF-κB in macrophages by adding doxycycline to the drinking water of mice. We have combined these novel transgenics with the polyoma model of mammary cancer for our studies. We have recently shown that activation of NF-κB in macrophages significantly limits metastasis in a tail vein model of tumor progression. In this model, constitutive IKK2 activity within macrophages leads to an anti-tumor immune response including altered immune cell populations within the lung microenvironment, changes in chemokine and cytokine expression and rapid killing of tumor cells during the seeding phase mediated by reactive oxygen species. Our current work has extended these findings to an orthotopic mammary tumor model. Again, we find that activation of NF-κB in macrophages results in decreased primary tumor growth and decreased tumor seeding into the blood. To model this activation in vitro, we have utilized immortalized bone marrow derived macrophages from IκBα knock-out mice compared to a wild type line. IκBα KO macrophages display changes in morphology and adhesion relative to wild type macrophages. This correlates with increased cytotoxic behavior in co-culture with polyoma tumor cells, mirroring the in vivo phenotype of the cIKK2 expressing macrophages. Given these findings, we believe that targeted activation of NF-κB signaling in macrophages could be harnessed to overcome the education of macrophages by tumor cells, and could be exploited as a novel targeted therapy. Citation Format: Whitney Barham, Oleg Tikhomirov, Lianyi Chen, Ryan Ortega, Linda Gleaves, Halina Onishko, Taylor Sherrill, Linda Connelly, Timothy S. Blackwell, Fiona E. Yull. Education of macrophages through modulation of NF-kappaB: an opportunity for targeted therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1545. doi:10.1158/1538-7445.AM2013-1545