Abstract
HIFU has been demonstrated to enhance anti-tumor immunity, however, the mechanism of which has not been well elucidated. Emerging evidence indicates that miRNAs play important roles in immune response. In this study, we used the B16F10 melanoma allograft mouse model to investigate the role of miRNAs in HIFU-enhanced anti-tumor immunity. We found that HIFU treatment decreased circulating B16F10 cells and pulmonary metastasis nodules while increased IFN-γ and TNF-α in the peripheral blood and cumulative mouse survival, which was associated with inhibition of miR-134 expression and activation of CD86 expression in tumor tissues. Further, we determined that miR-134 directly binds to the 3'UTR of CD86 mRNA to suppress its expression in B16F10 cells. When B16F10 cells transfected with miR-134 were co-cultured with normal splenic lymphocytes, the secretion of IFN-γ and TNF-α from lymphocytes was reduced and B16F10 cell survival was increased. HIFU exposure efficiently decreased miR-134 while increased CD86 expression in B16F10 cells in vitro. CD86 knockdown with siRNA markedly rescued the viability of HIFU-treated B16F10 cells that co-cultured with lymphocytes. Altogether, our results suggest that HIFU down-regulates miR-134 to release the inhibition of miR-134 on CD86 in melanoma cells, thereby enhancing anti-tumor immune response.
Highlights
High-intensity focused ultrasound (HIFU) is an emerging non-invasive ablation technique that takes advantage of the ultrasonic wave to target tumor entities, causing protein degeneration and coagulative necrosis of tumor tissue
We found that HIFU treatment decreased circulating B16F10 cells and pulmonary metastasis nodules while increased IFN-γ and TNF-α in the peripheral blood and cumulative mouse survival, which was associated with inhibition of miR-134 expression and activation of CD86 expression in tumor tissues
The cumulative survival rate of HIFU-treated mice was statistically higher than that of the control (p < 0.01, Figure 1E). These experiments show that HIFU could suppress tumor growth and distant metastasis, and improve host survival, suggesting that HIFU treatment could be a good choice for melanoma therapy
Summary
High-intensity focused ultrasound (HIFU) is an emerging non-invasive ablation technique that takes advantage of the ultrasonic wave to target tumor entities, causing protein degeneration and coagulative necrosis of tumor tissue. HIFU has been shown to improve the prognosis of patients with malignant tumors such as pancreatic and prostate cancer and melanoma [1, 2]. In the past few years, it was found that HIFU eradicates primary tumors, inhibits tumor relapse and distant metastasis, it triggers systemic anti-tumor immunity [3, 4]. There are different views and hypotheses about the mechanism of HIFU-evoked anti-tumor immunity. HIFU may effectively decrease tumor loads to restore immune system function [5]. HIFU-induced oncolysis may lead to the release of tumorassociated antigens [6, 7]. HIFU induces the release of heat shock protein to stimulate the host immune system [8].
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