Breast cancer that recurs as metastatic disease many years after primary tumor resection and adjuvant therapy appears to arise from tumor cells that disseminated early in the course of the disease but did not develop into clinically apparent lesions. These long-term surviving, quiescent disseminated dormant tumor cells (QDTC) are resistant to conventional therapies that target actively dividing cells. The mechanisms responsible for maintaining the survival and outgrowth of QDTC remain largely unknown. Recently, we found that fibrotic-like microenvironment with extensive deposition of Type I collagen (Col-I) and fibroectin, established at the site of the residing QDTC, promoted the outbreak of QDTC. Therefore, we hypothesized that promoting resolution—the endogenous mechanism that terminates inflammation and fibrotic responses and actively directs tissue return to homeostasis—at the permissive site will “normalize” it and prevent metastatic outbreak. Here we demonstrate that soluble factors secreted by ex vivo generated pro-resolving CD11blow macrophages can inhibit the establishment of a fibrotic niche resulting in the inhibition of the metastatic outgrowth of QDTC. The inhibition of the fibrotic niche was due to inhibition of TGFβ1-induced differentiation of fibroblasts to myofibroblasts and myofibroblasts’ apoptosis. Interestingly, our data also demonstrate that the blockade of fibroblast differentiation to myofibroblasts is not mediated by inhibition of the canonical signaling of TGFβ1. Taken together our results demonstrate a pioneering conceptual approach to “normalize” the microenvironment that supports the outgrowth of QDTC by promoting the tissue resolution axis.
This abstract is also being presented as Poster B36.
Citation Format: Odelya Gilon, Yonatan David Feuermann, Sagie Schif-Zuck, Keren Weidenfeld, Palle Von Huth, Edmond Sabo, Amiram Ariel, Dalit Barkan. Preventing the recurrence of breast cancer at the metastatic niche using resolution-phase macrophages [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr PR05.