Investigation of HIFU-induced anti-tumor immunity in a murine tumor model

Abstract

Background: High intensity focused ultrasound (HIFU) is an emerging non-invasive treatment modality for localized treatment of cancers. While current clinical strategies employ HIFU exclusively for thermal ablation of the target sites, biological responses associated with both thermal and mechanical damage from focused ultrasound have not been thoroughly investigated. In particular, endogenous danger signals from HIFU-damaged tumor cells may trigger the activation of dendritic cells. This response may play a critical role in a HIFU-elicited anti-tumor immune response which can be harnessed for more effective treatment.

Sonoluminescence and sonochemiluminescence study of cavitation field in a 1.2MHz focused ultrasound

“…In early HIFU clinical application, acoustic cavitation was generally avoided due to its unpredictable lesion shapes [3]. However, recent researchers suggest that acoustic cavitation can be used to enhance HIFU-induced ablation [4]. Furthermore, acoustic cavitation is considered to be the primary mechanism for tissue erosion [5] and histotripsy [6], which offer effective techniques to remove tissue precisely in clinical treatments.…”

Ultrasound-Based Therapies for the Treatment of Cancer

“…Thermal HIFU ablation increases CD4 257,260,264,358 and CD8 252,260-262 cell infiltration within treated tumors. 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 .…”

“…Conflicting studies report that HIFU may either increase 245 or decrease 251 the release of VEGF and TGFβ, although it should be noted that these studies were done in different cancer types. Given the functions of these molecules, it should not be surprising that HIFU-treated tumors show significant increases in DC and macrophage activation and infiltration 246,[252][253][254][255] , NK cell activity 253,256 , CD4 and CD8 T cell infiltration 18,251,252,[256][257][258][259][260][261][262][263] and improvements in CD4/CD8 T cell ratios 18,251,256,260,264 . In preclinical models, animals demonstrated resistance to tumor rechallenge following HIFU treatment 251,258,263 , indicating that a memory response had been generated against the treated tumors.…”

“…Interestingly, sparse-scan 254 or mechanical ablation 246,258,263 techniques, which either leave part of the tumor intact or do not thermally denature tumor antigens, showed improvements in activation of antigen presenting cells and increases in CD8 T cell activity when compared to thermal ablation of the entire tumor mass. These observations, in conjunction with tumor rechallenge experiments, provide strong evidence that HIFU-induced antitumor immunity is an antigen-mediated response 265 .…”

“…High intensity focused ultrasound (HIFU) ablation has been associated with antitumor immune responses in several types of cancer, including pancreatic 358 , prostate 243,244,263 , colon 258 , kidney 252,264 and breast 253,359 . 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 .…”