The abscopal effects of sonodynamic therapy in cancer

Abstract

The abscopal effect is a phenomenon wherein localised therapy on the primary tumour leads to regression of distal metastatic growths. Interestingly, various pre-clinical studies utilising sonodynamic therapy (SDT) have reported significant abscopal effects, however, the mechanism remains largely enigmatic. SDT is an emerging non-invasive cancer treatment that uses focussed ultrasound (FUS) and a sonosensitiser to induce tumour cell death. To expand our understanding of abscopal effects of SDT, we have summarised the preclinical studies that have found SDT-induced abscopal responses across various cancer models, using diverse combination strategies with nanomaterials, microbubbles, chemotherapy, and immune checkpoint inhibitors. Additionally, we shed light on the molecular and immunological mechanisms underpinning SDT-induced primary and metastatic tumour cell death, as well as the role and efficacy of different sonosensitisers. Notably, the observed abscopal effects underscore the need for continued investigation into the SDT-induced 'vaccine-effect' as a potential strategy for enhancing systemic anti-tumour immunity and combating metastatic disease. The results of the first SDT human clinical trials are much awaited and are hoped to enable the further evaluation of the safety and efficacy of SDT, paving the way for future studies specifically designed to explore the potential of translating SDT-induced abscopal effects into clinical reality.

Fig. 1. Effect of sonosensitiser activation.

Through various mechanisms, low intensity focussed ultrasound activates sonosensitisers causing cellular stress in cancer cells through increased mechanical disruption and generation of reactive oxygen species (ROS). Mechanical disruption itself can precipitate cell lysis and in response, release of interferon-gamma (IFN-γ) and tumour necrosis factor alpha (TNF-α). Build-up of intracellular ROS can trigger immunogenic cell death leading to release of tumour associated antigens (TAAs) and damage-associated molecular patterns (DAMPs).

Fig. 2. Process of immunogenic cell death.

Once immunogenic cell death is activated, damage-associated molecular patterns (DAMPs) are released. Calreticulin exposure and externalisation of phosphatidylserine on the surface of the stressed cell act as to signal local immature dendritic cells. High motility group box 1 (HMGB1) protein release binds to pattern recognition receptors (PRRs) to increase inflammation. Extracellular ATP simultaneously acts as a ‘find-me’ signal itself and also activates purinergic P2X₇ receptors on dendritic cells. Heat shock proteins generated secondary to cellular stress also contribute to the activation of dendritic cells. Once the immature dendritic cells are activated and phagocytose cellular fragments, tumour associated antigens (TAAs) become present on the major histocompatibility complexes leading to antigen presentation, maturation and tumour antigen response.

Fig. 3. Immune cascade.

The activation and maturation of dendritic cells are the first step in the immune cascade that causes the abscopal effect. Immature dendritic cells (iDCs) migrate to primary lymphoid organs where they mature. Following this, they prime naive T cells and trigger clonal expansion.

Fig. 4. Immune stimulation by SDT.

The ultrasound activated sonosensitiser triggers cell death both from mechanical disruption and generation of ROS. This triggers multiple pathways of immune cell activation to generate a coordinated and targeted immune response sensitive to both the primary tumour and metastatic lesions.

Fig. 5. Tumour growth inhibition after 6 SDT cycles.

HiPorfin (HPD) combined with ultrasound irradiation effectively inhibited tumour growth in bilateral liver cancer mouse models (P < 0.001, vs control). Data expressed as means ± SD (n = 10). Figure from Zhang et al. [91] under Creative Commons license.