Investigation of the Potential Immunological Effects of Boiling Histotripsy for Cancer Treatment

Abstract

Boiling histotripsy (BH) is a completely non-invasiveultrasonic technique that can be used to mechanically destroy tumor tissues. Studies have shown that BH has biological effects on immune responses, but the mechanisms involved in the induction and enhancement of systemic anti-tumor immune responses after BH treatment are poorly understood. The present study therefore investigates the anti-tumor immune responses triggered by BH exposure in vivo. In a syngeneic tumor model, BH treatment results in more dendritic cell maturation and increased intra-tumoral infiltration of activated CD8 + T cells compared to those observed after thermal high-intensity focused ultrasound exposure. The results clearly show that tumor antigens and danger signals released after BH exposure can lead to a sufficient anti-tumor immune response with antigen-presenting cell activation. In the 4T1 triple-negative breast cancer model, BH-induced mechanical ablation further enhances the therapeutic effect of immune checkpoint blockade, indicating a synergistic anti-tumor immune effect. In conclusion, the results presented in this study suggest that BH is a promising option for boosting anti-tumor immunity and can be beneficially combined with cancer immunotherapy.

Therapeutic Ultrasound-Enhanced Immune Checkpoint Inhibitor Therapy

“…These findings [13][14][15][16] suggest that HIFU mechanical ablation alone, without the need for adjuvants, is sufficient to enhance ICI therapy for the treatment of cancers that are unresponsive to ICIs. One advantage of HIFU mechanical ablation over HIFU thermal ablation is that tumor fragmentation instead of tumor coagulation may protect TAAs and DAMPs from protein denaturation by excessive heat and stimulate more effective antitumor immune responses [15,16,33,41].…”

“…Notably, the combination therapy improved long-term survival, achieved complete bilateral tumor regression, and induced an effective long-term immune memory response to suppress subsequent tumor engraftment. Other recent studies found that histotripsy stimulated more potent intratumoral CD8 T cells and antigen presentation than HIFU thermal ablation in a murine breast cancer model [15] and melanoma model [16]. One recent study showed that combining histotripsy with intratumor anti-CD40 agonist antibody, αCTLA-4, and anti-PD-L1 antibody (αPD-L1) significantly improved the therapeutic efficacy against ICI refractory murine melanoma [17].…”

“…As a promising therapeutic technology, FUS has the unique combined advantages of being noninvasive, nonionizing, nonpharmaceutical, spatially targeted, and deeply penetrating the body. Since 2017, five FUS modalities, including highintensity focused ultrasound (HIFU) thermal ablation [7][8][9][10][11], HIFU hyperthermia [12], HIFU mechanical ablation [13][14][15][16][17], ultrasound-targeted microbubble destruction (UTMD) [18][19][20], and sonodynamic therapy (SDT) [21,22], have been investigated in combination with ICIs for treating solid tumors in mouse models. The enhancement of antitumor immune responses by these FUS modalities demonstrated the great promise of FUS as a transformative cancer treatment modality to improve ICI therapy.…”

Chemotherapy and Physical Therapeutics Modulate Antigens on Cancer Cells

“…Boiling histotripsy of the tumor tissue via the application of ultrasounds is similar to the effects of IRE ( 248 ). The mechanism is similar and the methods seem complimentary and both modulate the immunophenotype of CD8+ cells to a phenotype which is more cytotoxic toward cancer cells.…”

Destruction of Tumor Microenvironment as a Promising Treatment Approach in Pancreatic Cancer

“…Histotripsy is a novel, non-thermal, image guided ablation modality using pulsing regimens to generate cavitation bubble clouds that lead to precise non-thermal tumor ablation that can rapidly kill cells in a targeted region with millimeter precision [60]. Several works established that there is an immune response to histotripsy ablation in many tumors, however a definite mechanism behind this response has not been established [61][62][63].…”