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Theranostics 2024; 14(4):1647-1661. doi:10.7150/thno.92089 This issue Cite

Research Paper

Focused ultrasound ablation of melanoma with boiling histotripsy yields abscopal tumor control and antigen-dependent dendritic cell activation

Eric A. Thim^1,†, Lydia E. Kitelinger^2,†, Fátima Rivera-Escalera³, Alexander S. Mathew¹, Michael R. Elliott³, Timothy N. J. Bullock^2,✉, Richard J. Price^1,✉

1. Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.
2. Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
3. Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.
†. These authors contributed equally: E. Andrew Thim and Lydia E. Kitelinger.

✉ Corresponding authors: Richard J. Price, Ph.D., Department of Biomedical Engineering, Box 800759, Health System, University of Virginia, Charlottesville, VA 22908, USA; Telephone: (434) 924-0020; Email: rpriceedu; ORCID: 0000-0002-0237-2102. Timothy N. J. Bullock, Ph.D., Department of Pathology, Box 801386, Health System, University of Virginia, Charlottesville, VA 22908, USA; Telephone: (434) 982-1932; Email: tb5vedu; ORCID: 0000-0001-6141-3261. More

Abstract

Background: Boiling histotripsy (BH), a mechanical focused ultrasound ablation strategy, can elicit intriguing signatures of anti-tumor immunity. However, the influence of BH on dendritic cell function is unknown, compromising our ability to optimally combine BH with immunotherapies to control metastatic disease.

Methods: BH was applied using a sparse scan (1 mm spacing between sonications) protocol to B16F10-ZsGreen melanoma in bilateral and unilateral settings. Ipsilateral and contralateral tumor growth was measured. Flow cytometry was used to track ZsGreen antigen and assess how BH drives dendritic cell behavior.

Results: BH monotherapy elicited ipsilateral and abscopal tumor control in this highly aggressive model. Tumor antigen presence in immune cells in the tumor-draining lymph nodes (TDLNs) was ~3-fold greater at 24h after BH, but this abated by 96h. B cells, macrophages, monocytes, granulocytes, and both conventional dendritic cell subsets (i.e. cDC1s and cDC2s) acquired markedly more antigen with BH. BH drove activation of both cDC subsets, with activation being dependent upon tumor antigen acquisition. Our data also suggest that BH-liberated tumor antigen is complexed with damage-associated molecular patterns (DAMPs) and that cDCs do not traffic to the TDLN with antigen. Rather, they acquire antigen as it flows through afferent lymph vessels into the TDLN.

Conclusion: When applied with a sparse scan protocol, BH monotherapy elicits abscopal melanoma control and shapes dendritic cell function through several previously unappreciated mechanisms. These results offer new insight into how to best combine BH with immunotherapies for the treatment of metastatic melanoma.

Keywords: focused ultrasound, boiling histotripsy, immunotherapy, dendritic cells, tumor antigen

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