(460g) Invited Talk: Engineered Tissue Models to Study Radiation-Induced Tumor and Immune Cell Recruitment

Triple negative breast cancer (TNBC) recurrence rates remain high despite aggressive therapeutic intervention, including surgery, chemotherapy, and radiotherapy (RT). Recent studies suggest that circulating tumor cell re-seeding of primary tumors may enable recurrence rather than persistent tumor cells in the irradiated surgical bed. However, the role of the microenvironment in recurrence is not well understood. We studied the influence of the immune system in tumor cell recruitment to radiation-damaged sites. We characterized the effects of normal tissue irradiation on tumor and immune cell migration. We found that RT stimulates tumor cell recruitment in immunocompromised mice and that CD8+ T cells inhibit tumor cell migration to normal tissues. Tumor cell recruitment was shown to be coupled with excess macrophage infiltration. Our in vivo results informed the design of engineered mammary spheroids and extracellular matrix hydrogels. Through these tissue models, we determined that radiation facilitates normal tissue damage that enhances immune cell infiltration as well as tumor cell proliferation and invasion. Taken together, these results indicate that irradiation of normal tissues may produce a microenvironment suitable for tumor cell recruitment, retention, and proliferation, especially under immunosuppressed conditions. Our work suggests that the tumor stroma may enable TNBC cell recruitment and regrowth following RT in immunocompromised patients. This study represents an important step toward elucidating the contribution of stromal cells and immune status to local recurrence following therapy in breast cancer. Future studies will utilize these results to engineer improved in vitro tumor and tissue microenvironment models to probe the complex physical, chemical, and biological cues that promote TNBC recurrence and metastasis.