Low-pressure pulsed focused ultrasound with microbubbles promotes an anticancer immunological response

Abstract

BackgroundHigh-intensity focused-ultrasound (HIFU) has been successfully employed for thermal ablation of tumors in clinical settings. Continuous- or pulsed-mode HIFU may also induce a host antitumor immune response, mainly through expansion of antigen-presenting cells in response to increased cellular debris and through increased macrophage activation/infiltration. Here we demonstrated that another form of focused ultrasound delivery, using low-pressure, pulsed-mode exposure in the presence of microbubbles (MBs), may also trigger an antitumor immunological response and inhibit tumor growth.MethodsA total of 280 tumor-bearing animals were subjected to sonographically-guided FUS. Implanted tumors were exposed to low-pressure FUS (0.6 to 1.4 MPa) with MBs to increase the permeability of tumor microvasculature.ResultsTumor progression was suppressed by both 0.6 and 1.4-MPa MB-enhanced FUS exposures. We observed a transient increase in infiltration of non-T regulatory (non-Treg) tumor infiltrating lymphocytes (TILs) and continual infiltration of CD8+ cytotoxic T-lymphocytes (CTL). The ratio of CD8+/Treg increased significantly and tumor growth was inhibited.ConclusionsOur findings suggest that low-pressure FUS exposure with MBs may constitute a useful tool for triggering an anticancer immune response, for potential cancer immunotherapy.

High intensity focused ultrasound (HIFU) applied to hepato-bilio-pancreatic and the digestive system—current state of the art and future perspectives

“…Among non-thermal effects, the transfer of mechanical energy seems to be able to induce cascade phenomena that could profoundly affect the host response. A most intriguing phenomenon is the modulation of immune-response: the disintegration of neoplastic masses induced by vibration seems to enhance the anti-tumor immune-surveillance by amplification of cancer antigens (81,82). Zhou et al demonstrated a significant decrease of immunosuppressive cytokines after HIFU, which means a shift towards improved anti-cancer immune response (23).…”

Ultrasound-Based Therapies for the Treatment of Cancer

“…Mechanical ablation 246,258,263 and sparse-scan ablation protocols 254 that do not fully denature tumor antigens improve antigen presenting cell (APC) activation compared to thermal protocols, indicating that non-thermal approaches may be more effective in generating an antigen-specific systemic antitumor response. Furthermore, low intensity pulsed ultrasound with microbubbles (US) has been shown to enhance delivery of NK cells to tumors 266 , increase T cell infiltration in response to ultrasound-induced tumor ischemia 268 , and increase the CD8/Treg ratio while providing modest tumor growth control 267 . Our results with US, demonstrating improved tumor growth control, increased CD4, CD8, and NK populations, and increased CD8/Treg ratios, agree nicely with this body of work and further support the hypothesis that US should synergize with PD-1 therapy.…”

“…The CD8/Treg ratio was significantly improved by day 3 and remained elevated at day 18. 267 Given the pressures used and the marked enhancement in dextran permeability, it is certain that this protocol produced vascular disruption within the tumor. Hunt et al utilized low-power US in combination with microbubbles in a protocol designed to decreased tumor perfusion, under the assumption that antivascular therapy can induce a hypoxia-mediated immune response.…”

“…Although the immune response following tumor ablation with HIFU is fairly well characterized 253,254,265 , the immune response following low-intensity ultrasound and microbubble therapy is poorly documented and the mechanisms are unknown 267,268 . Additionally, no one has yet attempted to determine the relative contributions of the innate and adaptive immune systems, or T cell trafficking versus proliferation, following either high or low-intensity ultrasound.…”

“…However, recent studies have shown that mechanical ablation 258 or partial thermal ablation 254 produce a more powerful antitumor immune response, indicating that techniques which enhance tumor antigen exposure without causing heat denaturation of the tumor tissue may be more efficacious. Low intensity ultrasound and microbubble therapy has been shown to enhance the delivery of immune cells to tumors 266 , induce hypoxic cell death due to decreased perfusion 268 , and enhance tumor resident CD4 and CD8 T cell populations 267 . However, the mechanisms are poorly understood.…”