Immune modulation resulting from MR-guided high intensity focused ultrasound in a model of murine breast cancer

Abstract

High intensity focused ultrasound (HIFU) rapidly and non-invasively destroys tumor tissue. Here, we sought to assess the immunomodulatory effects of MR-guided HIFU and its combination with the innate immune agonist CpG and checkpoint inhibitor anti-PD-1. Mice with multi-focal breast cancer underwent ablation with a parameter set designed to achieve mechanical disruption with minimal thermal dose or a protocol in which tumor temperature reached 65 °C. Mice received either HIFU alone or were primed with the toll-like receptor 9 agonist CpG and the checkpoint modulator anti-PD-1. Both mechanical HIFU and thermal ablation induced a potent inflammatory response with increased expression of Nlrp3, Jun, Mefv, Il6 and Il1β and alterations in macrophage polarization compared to control. Furthermore, HIFU upregulated multiple innate immune receptors and immune pathways, including Nod1, Nlrp3, Aim2, Ctsb, Tlr1/2/4/7/8/9, Oas2, and RhoA. The inflammatory response was largely sterile and consistent with wound-healing. Priming with CpG attenuated Il6 and Nlrp3 expression, further upregulated expression of Nod2, Oas2, RhoA, Pycard, Tlr1/2 and Il12, and enhanced T-cell number and activation while polarizing macrophages to an anti-tumor phenotype. The tumor-specific antigen, cytokines and cell debris liberated by HIFU enhance response to innate immune agonists.

HSP90 inhibition acts synergistically with heat to induce a pro-immunogenic form of cell death in colon cancer cells

“…Checkpoint inhibitor immunotherapy could then maximize the anti-cancer immune response, as has been shown for anti-PD-1 treated, AUY922-sensitised melanoma tumors [44]. The results of this study also contribute to efforts to define the most appropriate thermal doses for inducing an anticancer immune response [86,87], and show that the use of precise sub-ablative TIDs, as shown here and elsewhere [57][58][59], with well-defined biological and immunological outcomes, can, not only maximize treatment response but also increase the pro-immune phenotype of the cancer cells, thus providing added value when used in combination with the latest immunotherapies.…”

Therapeutic Ultrasound-Enhanced Immune Checkpoint Inhibitor Therapy

“…HIFU thermal ablation as a combination therapy with ICIs has the potential limitation that excessive heat generation by HIFU thermal ablation may induce protein denaturation and inactivate antigen presentation [13]. Meanwhile, HIFU thermal ablation was also reported to increase tumor infiltrated MDSCs and Tregs at both directly treated and distant tumors, leading to inhibition of antitumor immunotherapy [11]. These negative effects highlight the complexity of combining HIFU thermal ablation with ICI therapy.…”

“…These reported studies [7,9,10,12] suggest that neither HIFU thermal ablation nor HIFU hyperthermia alone is sufficient to enhance ICI efficacy in murine tumor models. Both FUS modalities were found to enhance the release of TAAs and recruitment of CD8 T cells, but in the absence of additional stimuli (e.g., adjuvants, chemotherapeutics), the recruited CD8 T cells might not have sufficient antigen cross-presentation and cross-priming mediated by DCs and macrophages [8,11]. Future studies are needed to investigate the optimal combination therapy by HIFU thermal ablation or hyperthermia with ICIs and adjuvants/chemotherapeutics to achieve systemic, long-term effects for cancer treatment.…”

“…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.…”

Development of a Systematic Review Protocol and a Scoping Review of Ultrasound-Induced Immune Effects in Peripheral Tumors

“…The majority (13/15) of included publications used mice, whereas two showed results of female human breast cancer patients aged 46-47 years [36,37]. Regarding publications performed in mice, female mice were used in 76.92 % (11/13) of publications [38][39][40][41][42][43][44][45][46][47]. Furthermore, one publication was performed with male mice (7.69 %) [48], and two publications did not report the mice's sex (15.38 %) [49,50] (Fig.…”