Abstract
Boiling histotripsy is a promising non-invasive High-Intensity Focused Ultrasound (HIFU) technique that employs HIFU mechanical effects to fractionate solid tumours without causing any significant thermal damage. It has been suggested that boiling histotripsy may induce a strong immune response due to the absence of denatured antigenic protein at the HIFU focus. The underlying immunological mechanisms of this technique are, however, poorly understood. In this study, we demonstrated the feasibility of using boiling histotripsy to mechanically fractionate human breast adenocarcinoma cells (MDA-MB-231) and the potential immunological effects induced by boiling histotripsy, for the first time. Our results showed that mechanical stresses produced by boiling histotripsy promote immunogenic cell death of cancer cells via TNF-induced necrosis signaling pathway. This immunogenic cell death significantly increases secretions of damage-associated molecular patterns (CRT, HSP70, HMGB-1), pro-inflammatory cytokines (IFN-γ, IL-1α, IL-1β, IL-18) and chemokines (IL-8) which are related to M1 macrophage activation. Furthermore, the levels of these signaling proteins increase with the degree of mechanical damage induced by boiling histotripsy. Together, the results presented can suggest that boiling histotripsy could be a potential therapeutic approach for not only mechanically destroying solid tumours (e.g., breast cancer) but also promoting immunogenic cell death via TNF-induced necrosis to trigger antitumour immunity.
Highlights
Heart and liver which are sharply demarcated between treated and untreated regions without any sign of thermal damage[7,8,9,10,11]
This was performed to investigate whether mechanical damage can be induced in the collagen gel with the High-Intensity Focused Ultrasound (HIFU) exposure conditions used in the present study
A well-defined “tadpole” shaped-mechanically fractionated lesion filled with liquid was clearly observed at the HIFU focus in the gel, which is a characteristic of boiling histotripsy exposure[22,29,30]
Summary
Heart and liver which are sharply demarcated between treated and untreated regions without any sign of thermal damage[7,8,9,10,11]. Whilst most studies have shown the potential immunological effects of HIFU thermal ablation, some studies suggest that HIFU-induced mechanical effects may even induce a stronger immune response. Schade et al.[20] recently found that boiling histotripsy can significantly increase anti-tumour immunity through acute inflammatory and immunologic responses to mechanical ablation of renal cell carcinoma in vivo. Though they clearly demonstrated the high potential of boiling histotripsy for triggering an immune response for the first time, the mechanisms behind the enhancement of antitumour activities following boiling histotripsy treatment are still poorly understood, intracellular signalling cascades that can eventually lead to the generation of pro-inflammatory tumour microenvironment. In vitro experiments with human breast adenocarcinoma cells (MDA-MB-231) are performed in the present study
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