Focused ultrasound ablation as an immunomodulatory strategy for metastatic breast cancer therapy

Abstract Metastatic breast cancer (BrCa) is incurable, with a 5 year survival of only 22%. While immunotherapies are capable of generating durable responses in many forms of cancer, immune rejection of BrCa is very rare. Indeed, immunotherapies (e.g. checkpoint blockade) for BrCa are limited by poor functional CD8+ T cell infiltration and immunosuppression in the tumor microenvironment. Thus, adjunct strategies that render BrCa tumors responsive to immunotherapies are desperately needed. Focused ultrasound (FUS) mediates noninvasive acoustic energy deposition into tumors, conferring localized thermal and mechanical damage to targeted tissue. Here, we tested the hypothesis that FUS thermal ablation (TA) can serve as an auto-vaccine for treatment of BrCa with immunotherapy. Murine mammary carcinoma (4T1-HA) tumors were partially ablated with a 3 MHz ultrasound-guided FUS system. In tumor-draining lymph nodes, 1 week after FUS, we observed a ~3-fold increase in mature dendritic cells (CD11c-hi/CD86+), as well as an increasing trend in M1 macrophage representation by flow cytometry. While FUS did not confer changes in intratumoral CD8+ and CD4+ T cells, likely due to an overwhelming immunosuppressive burden imposed by myeloid derived suppressor cells (MDSCs), infiltrating T cells did express PD1. Therefore, we developed a combination treatment approach of FUS + gemcitabine and/or anti-PD1. This combination treatment elicited an ~50% reduction in 4T1-HA tumor growth at 5 days post-FUS ablation, suggesting that partial TA of BrCa tumors with FUS may represent a promising immunoadjuvant approach. Taken together, these results suggest immunoadjuvants abrogating immunosuppression may enable FUS to stimulate anti-tumor immunity in BrCa.