Combination of thermally ablative focused ultrasound with gemcitabine controls breast cancer via adaptive immunity.
BACKGROUND
Triple-negative breast cancer (TNBC) remains recalcitrant to most targeted therapy approaches. However, recent clinical studies suggest that inducing tumor damage can render TNBC responsive to immunotherapy. We therefore tested a strategy for immune sensitization of murine TNBC (4T1 tumors) through combination of focused ultrasound (FUS) thermal ablation and a chemotherapy, gemcitabine (GEM), known to attenuate myeloid-derived suppressor cells (MDSCs).


METHODS
We applied a sparse-scan thermally ablative FUS regimen at the tumor site in combination with systemically administered GEM. We used flow cytometry analysis to investigate the roles of monotherapy and combinatorial therapy in mediating local and systemic immunity. We also tested this combination in Rag1-/- mice or T cell-depleted wild-type mice to determine the essentiality of adaptive immunity. Further, we layered Programmed cell death protein 1 (PD-1) blockade onto this combination to evaluate its impact on tumor outgrowth and survival.


RESULTS
The immune-modulatory effect of FUS monotherapy was insufficient to promote a robust T cell response against 4T1, consistent with the dominant MDSC-driven immunosuppression evident in this model. The combination of FUS+GEM significantly constrained primary TNBC tumor outgrowth and extended overall survival of mice. Tumor control correlated with increased circulating antigen-experienced T cells and was entirely dependent on T cell-mediated immunity. The ability of FUS+GEM to control primary tumor outgrowth was moderately enhanced by either neoadjuvant or adjuvant treatment with anti-PD-1.


CONCLUSION
Thermally ablative FUS in combination with GEM restricts primary tumor outgrowth, improves survival and enhances immunogenicity in a murine metastatic TNBC model. This treatment strategy promises a novel option for potentiating the role of FUS in immunotherapy of metastatic TNBC and is worthy of future clinical evaluation.


TRIAL REGISTRATION NUMBERS
NCT03237572 and NCT04116320.
['Sheybani|Natasha D|ND|', 'Witter|Alexandra R|AR|', 'Thim|Eric A|EA|', 'Yagita|Hideo|H|', 'Bullock|Timothy N J|TNJ|0000-0001-6141-3261', 'Price|Richard J|RJ|0000-0002-0237-2102']
D056704:Adaptive Immunity D003841:Deoxycytidine D005260:Female D057086:High-Intensity Focused Ultrasound Ablation D006801:Humans D007166:Immunosuppressive Agents D064726:Triple Negative Breast Neoplasms
adaptive immunity immunotherapy breast neoplasms combined modality therapy