Irradiated Mammary Spheroids Elucidate Mechanisms of Macrophage-Mediated Breast Cancer Recurrence

While most patients with triple negative breast cancer receive radiotherapy to improve outcomes, a significant subset of patients continue to experience recurrence. Macrophage infiltration into radiation-damaged sites has been shown to promote breast cancer recurrence in pre-clinical models. However, the mechanisms that drive recurrence are unknown. Here, we developed a novel spheroid model to evaluate macrophage-mediated tumor cell recruitment. We first characterized infiltrating macrophage phenotypes into irradiated mammary tissue to inform our model. We then established spheroids consisting of fibroblasts isolated from mouse mammary glands. We observed that tumor cell motility toward irradiated spheroids was enhanced in the presence of a 2:1 ratio of pro-healing:pro-inflammatory macrophages. We also measured a significant increase in interleukin 6 (IL-6) secretion after irradiation both in vivo and in our model. This secretion increased tumor cell invasiveness, and invasion was mitigated by neutralizing IL-6. Taken together, our work suggests that interactions between infiltrating macrophages and damaged stromal cells facilitates breast cancer recurrence through IL-6 signaling.