Abstract 734: Role of TGF-â in myeloid regulation of tumor-induced bone disease

Abstract

Abstract Bone is one of the most common metastatic sites for breast cancer, where nearly 70% of patients that die from disease have reported skeletal metastases upon autopsy. Specifically in the bone microenvironment, TGF-â has a complex role in the regulation of tumor growth and is critical for the initiation and continuation of bone destruction, an important parameter of tumor-induced disease. Previous publications have demonstrated that TGF-â can affect myeloid cells by increasing their expansion in the tumor microenvironment and modulating host immune surveillance, thus supporting a tumor promoting environment. Therefore, we hypothesize that inhibition of TGF-â will decrease tumor-induced bone disease by reducing myeloid expansion and tumor growth in bone. To address this we injected mice with the TGF-â inhibitory antibody, 1D11, one week prior to tumor inoculation and continuously treated until sacrifice where myeloid expansion and parameters of tumor-induced bone disease were measured. Two mouse models were used to assess the importance of the immune system, an immunodeficient model inoculated with human breast cancer cells (MDA-MB-231) and a syngeneic model using murine breast cancer cells (4T1). Flow cytometry analysis revealed that TGF-â inhibition decreased a triple positive myeloid population (CD11b+F4/80+Gr-1+) in mice sacrificed at day 28 by five percent. This triple positive myeloid cell population has been associated with supporting tumor progression. Surprisingly our flow cytometry analysis demonstrated that myeloid-derived suppressor cells (MDSCs: CD11b+GR-1+) remained unchanged when TGF-â was inhibited. Micro-CT analysis demonstrated that 1D11 treated mice had a 2-fold increase in bone volume and connective density compared to control mice. X-ray analysis demonstrated that control mice had greater than 2-fold osteolytic bone destruction compared to mice treated with the TGF-â inhibitory antibody. Histomorphometric analyses suggests that TGF-â inhibition reduces tumor burden, increases osteoclast cell numbers and modulates macrophage cell populations. Together these results suggest that inhibiting TGF-â prior to tumor inoculation and subsequently after may prevent expansion of a tumor-promoting myeloid population and promote a bone-phenotype that does not support tumor growth in bone. Future studies will focus on investigating specific myeloid factors and assessing whether TGF-â inhibition decreases expression of these pro-tumorigenic factors. Citation Format: Denise Buenrostro, Alyssa Merkel, Julie Sterling. Role of TGF-â in myeloid regulation of tumor-induced bone disease. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 734.