High intensity focused ultrasound enhances anti-tumor immunity through promoting CD4 Th1 effector T cell response

  • Haiying Zhang Department of Renal Rheumatism, Shanghai Jiaotong University Affiliated Sixth People’s Hospital East Campus, NO.222 Huanhu West 3rd Road, Nanhui New Town, Pudong New District, Shanghai 201306, China
  • Kun Han Department of Renal Rheumatism, Shanghai Jiaotong University Affiliated Sixth People’s Hospital East Campus, NO.222 Huanhu West 3rd Road, Nanhui New Town, Pudong New District, Shanghai 201306, China
Keywords: Melanoma, HIFU, Anti-tumor immunity, TGFβ, MicroRNA-9-5p


Background: Melanoma accounts for more than 80% of deaths from all dermatologic cancers, mainly due to its widespread metastasis. High intensity focused ultrasound (HIFU) is a promising technique for cancer therapy. Here, we investigated the efficacy of HIFU against melanoma and the underlying mechanisms.

Methods: A melanoma allograft mouse model was established to examine the tumor progression and survival rate. Anti-tumor immunity was determined by measuring cytokines, regulatory T cells (Tregs), Th17 cells and CD8+ effector T cells. Western blot, qPCR, RNAi and luciferase assay were performed to confirm the expression and regulation of microRNA (miR)-9-5p and transforming growth factor beta (TGF-β).

Results: HIFU exposure significantly suppressed melanoma growth and metastasis by activating interferon gamma (IFN-γ) secretion, inhibiting Tregs and Th17 cells, and stimulating CD8+ effector T cells. TGF-β was a direct target of miR-9-5p. The anti-tumor effect of HIFU might be mediated through the miR-9-5p/TGF-β pathway.

Conclusion: HIFU activates anti-tumor response and alters tumor microenvironment, which may serve as a potential therapeutic strategy for melanoma treatment.


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Miller AJ, Mihm MC, Jr. Melanoma. N Engl J Med. 2006;355:51-65.

Schadendorf D, van Akkooi ACJ, Berking C, Griewank KG, Gutzmer R, Hauschild A, et al. Melanoma. Lancet. 2018;392:971-984.

Zbytek B, Carlson JA, Granese J, Ross J, Mihm MC, Jr., Slominski A. Current concepts of metastasis in melanoma. Expert Rev Dermatol. 2008;3:569-585.

Dadras SS, Paul T, Bertoncini J, Brown LF, Muzikansky A, Jackson DG, et al. Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol. 2003;162:1951-1960.

Hsiao YH, Kuo SJ, Tsai HD, Chou MC, Yeh GP. Clinical application of high-intensity focused ultrasound in cancer therapy. J Cancer. 2016;7:225-231.

Maloney E, Hwang JH. Emerging HIFU applications in cancer therapy. Int J Hyperthermia. 2015;31:302-309.

Xiong LL, Hwang JH, Huang XB, Yao SS, He CJ, Ge XH, et al. Early clinical experience using high intensity focused ultrasound for palliation of inoperable pancreatic cancer. JOP. 2009;10:123-129.

Ritchie RW, Leslie T, Phillips R, Wu F, Illing R, ter Haar G, et al. Extracorporeal high intensity focused ultrasound for renal tumours: a 3-year follow-up. BJU Int. 2010;106:1004-1009.

Ng KK, Poon RT, Chan SC, Chok KS, Cheung TT, Tung H, et al. High-intensity focused ultrasound for hepatocellular carcinoma: a single-center experience. Ann Surg. 2011;253:981-987.

Li S, Wu PH. Magnetic resonance image-guided versus ultrasound-guided high-intensity focused ultrasound in the treatment of breast cancer. Chin J Cancer. 2013;32:441-452.

Uchida T, Tomonaga T, Kim H, Nakano M, Shoji S, Nagata Y, et al. Improved outcomes with advancements in high intensity focused ultrasound devices for the treatment of localized prostate cancer. J Urol. 2015;193:103-110.

Hu Z, Yang XY, Liu Y, Sankin GN, Pua EC, Morse MA, et al. Investigation of HIFU-induced anti-tumor immunity in a murine tumor model. J Transl Med. 2007;5:34.

Wu F, Zhou L, Chen WR. Host antitumour immune responses to HIFU ablation. Int J Hyperthermia. 2007;23:165-171.

Wang YN, Khokhlova T, Bailey M, Hwang JH, Khokhlova V. Histological and biochemical analysis of mechanical and thermal bioeffects in boiling histotripsy lesions induced by high intensity focused ultrasound. Ultrasound Med Biol. 2013;39:424-438.

Xia JZ, Xie FL, Ran LF, Xie XP, Fan YM, Wu F. High-intensity focused ultrasound tumor ablation activates autologous tumor-specific cytotoxic T lymphocytes. Ultrasound Med Biol. 2012;38:1363-1371.

Yuan SM, Li H, Yang M, Zha H, Sun H, Li XR, et al. High intensity focused ultrasound enhances anti-tumor immunity by inhibiting the negative regulatory effect of miR-134 on CD86 in a murine melanoma model. Oncotarget. 2015;6:37626-37637.

Fischer AH, Jacobson KA, Rose J, Zeller R. Hematoxylin and eosin staining of tissue and cell sections. CSH Protoc. 2008;2008:pdb prot4986.

Guo L, Zhang P, Chen Z, Xia H, Li S, Zhang Y, et al. Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression. J Clin Invest. 2017;127:4449-4461.

Doherty GM, Lange JR, Langstein HN, Alexander HR, Buresh CM, Norton JA. Evidence for IFN-gamma as a mediator of the lethality of endotoxin and tumor necrosis factor-alpha. J Immunol. 1992;149:1666-1670.

Detournay O, Schnitzler CE, Poole A, Weis VM. Regulation of cnidarian-dinoflagellate mutualisms: Evidence that activation of a host TGFbeta innate immune pathway promotes tolerance of the symbiont. Dev Comp Immunol. 2012;38:525-537.

Chalmin F, Mignot G, Bruchard M, Chevriaux A, Vegran F, Hichami A, et al. Stat3 and Gfi-1 transcription factors control Th17 cell immunosuppressive activity via the regulation of ectonucleotidase expression. Immunity. 2012;36:362-373.

Knochelmann HM, Dwyer CJ, Bailey SR, Amaya SM, Elston DM, Mazza-McCrann JM, et al. When worlds collide: Th17 and Treg cells in cancer and autoimmunity. Cell Mol Immunol. 2018;15:458-469.

Liu F, Hu Z, Qiu L, Hui C, Li C, Zhong P, et al. Boosting high-intensity focused ultrasound-induced anti-tumor immunity using a sparse-scan strategy that can more effectively promote dendritic cell maturation. J Transl Med. 2010;8:7.

Gonzalez H, Hagerling C, Werb Z. Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev. 2018;32:1267-1284.

Togashi Y, Shitara K, Nishikawa H. Regulatory T cells in cancer immunosuppression - implications for anticancer therapy. Nat Rev Clin Oncol. 2019;16:356-371.

Wang X, Sun J. High-intensity focused ultrasound in patients with late-stage pancreatic carcinoma. Chin Med J (Engl). 2002;115:1332-1335.

Zhang Y, Deng J, Feng J, Wu F. Enhancement of antitumor vaccine in ablated hepatocellular carcinoma by high-intensity focused ultrasound. World J Gastroenterol. 2010;16:3584-3591.

Lee HM, Nguyen DT, Lu LF. Progress and challenge of microRNA research in immunity. Front Genet. 2014;5:178.

Keswani T, Sarkar S, Sengupta A, Bhattacharyya A. Role of TGF-beta and IL-6 in dendritic cells, Treg and Th17 mediated immune response during experimental cerebral malaria. Cytokine. 2016;88:154-166.

Li M, Wan G, Yu H, Xiong W. High-intensity focused ultrasound inhibits invasion and metastasis of colon cancer cells by enhancing microRNA-124-mediated suppression of STAT3. FEBS Open Bio. 2019;9:1128-1136.

How to Cite
ZhangH., & HanK. (2020). High intensity focused ultrasound enhances anti-tumor immunity through promoting CD4 Th1 effector T cell response. STEMedicine, 1(4), e65. https://doi.org/10.37175/stemedicine.v1i4.65
Research articles