Abstract B44: The role of MDSCs in breast cancer dormancy and recurrence

Abstract

Abstract Tumor relapse and metastasis are a major cause of death in women with breast cancer. By the time of primary tumor diagnosis cancer has already metastasized, and patients have developed either metastatic tumors or dormant disseminated tumor cells (DTCs). Tumor dormancy is a specific stage in which residual cells remain inactive and therapy resistant, possibly due to quiescence, niche protection, or both. To understand the obstacles to overcome protumorigenic signaling stemming from microenvironment, we are utilizing various syngeneic model of residual disease/dormancy and recurrence. We found that myeloid-derived suppressor cells (MDSCs) are recruited to tumor following the FGFR-mTOR pathway activation and enhance tumor-initiating cells through direct contact by promoting Notch signaling in vitro. We have utilized a novel transgenic model, MMTV-WNT1-iFGFR1GFP (iFGFR1GFP), with an intact immune system to study residual disease, dormancy, and their relapse. We have generated primary tumors by transplanting and expanding spontaneous iFGFR1GFP tumors into fat pad of the glow-head mice. To induce dormancy, we have treated established tumors with BGJ398, a specific FGFR inhibitor for two weeks, a time at which they were barely palpable, followed by a further two weeks of recovery. Inhibition of FGFR results in residual disease, and cells remain in dormant stage for up to 4 months post-BGJ398 treatment. Additionally, the expression of GFP and luciferase reporters will facilitate both the localization and isolation of solitary DTCs at the metastatic sites (lung). Our results show that majority of GFP+ residual cells are Ki67 negative and form normal-like gland structures and there is a significant reorganization of tumor stroma. Our preliminary data suggest that Notch signaling is activated during recurrence. MDSCs are present at all stages, and their abundance increases as cells escape dormancy and relapse, suggesting that MDSCs may potentially promote Notch signaling and enhance recurrence. Single-cell sequencing of tumors at different stages has shown that MDSCs express Jagged-1 and are being recruited to tumor during the dormant stage. Blocking antibodies against Jagged-1 are being utilized to test if suppressing MDSCs will inhibit tumor recurrence. Our results show that anti-Jagged-1 antibody increases the time to relapse. Furthermore, we will perform tail vein injection of cells to investigate dormancy in lung, as well as resect primary tumors to enhance potential metastatic lesions’ growth. The impact of this research will be to provide potential early biomarkers to detect the presence of MDSCs in order to predict which patients might relapse as well as the discovery of combinatorial therapeutics to decrease tumor recurrence. Citation Format: Mahnaz Janghorban, Xiang Zhang, Jeffrey Rosen. The role of MDSCs in breast cancer dormancy and recurrence [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B44.