The treatment of tumors with focused ultrasound can stimulate the immune system and potentially enhance the body's ability to manage cancer.

Courtesy of the National Cancer Institute

When a tumor is ablated, the exposed proteins and cellular debris can act as antigens that trigger an increased immune response to the tumor, both locally and potentially at distant metastases1,2. Furthermore, thermal ablation may cause local inflammation, stimulate the recruitment of immune effector cells, and activate anti-tumor adaptive immunity, all of which can increase the body’s resistance to cancer3. Immunomodulation through focused ultrasound could non-invasively augment and enhance existing chemotherapy and immunotherapy treatments for the management of tumors. Depending on the “mode” of focused ultrasound used – thermal ablation, mild hyperthermia, or mechanical destruction – there may be a slightly different immune response. Yet each of these mechanisms is capable of initiating an immune response by releasing antigens and danger signals from cancer cells.

FUS Immunomodulation_smThere are three proposed methods by which focused ultrasound may induce an immunotherapeutic response. First, tumor cell are stressed via one of the three focused ultrasound modes, causing the up-regulation of danger signals such as heat shock proteins (HSP60 and 70) and ATP, which can act as tumor vaccines and increase the immunogenicity of the tumor4,5. Second, focused ultrasound mitigates tumor-induced immunosuppression by decreasing levels of immunosuppressive cytokines (e.g. VEGF, TGF-ß1, and TGF-ß2)6. Third, cancer cell destruction creates tumor debris that act as antigens for antigen presenting cells, enhancing the immune response. Tumor debris can activate dendritic cells7 and other anti-tumor adaptive immunity cells, such as CD8+ T cells3.

However, based on the research to date, this effect may not be strong enough to control tumor growth on its own. Researchers are investigating the use of focused ultrasound in combination with other cancer treatments such as immunotherapy drugs. Because of focused ultrasound’s ability to penetrate the blood brain barrier and other dense stroma, it is an attractive modality to potentially boost the effectiveness of immunotherapies in notoriously difficult to treat cancers. Additionally, research into immunotherapies has shown that they are more successful in patients who have a baseline immune response to the cancer, which focused ultrasound is well poised to provide8.

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References

[1] Finley DS, Pouliot F, Shuch B, Chin A, Pantuck A, Dekernion JB, et al. Ultrasound-based combination therapy: potential in urologic cancer. Expert Rev. Anticancer Ther. 2011;11:107–13.

[2] S. P. Haen, P. L. Pereira, H. R. Salih, H.-G. Rammensee, and C. Gouttefangeas, “More than just tumor destruction: immunomodulation by thermal ablation of cancer.,” Clin. & Dev. Immunol., vol. 2011, Dec. 2011.

[3] D. F. Rosberger, D. J. Coleman, R. Silverman, S. Woods, M. Rondeau, and S. Cunningham-Rundles, “Immunomodulation in choroidal melanoma: reversal of inverted CD4/CD8 ratios following treatment with ultrasonic hyperthermia.,” Biotechnol. Ther., vol. 5, no. 1–2, pp. 59–68, 1994.

[4] Hu Z, Yang XY, Liu Y, Morse MA, Lyerly HK, Clay TM, et al. Release of endogenous danger signals from HIFU-treated tumor cells and their stimulatory effects on APCs. Biochem. Biophys. Res. Commun. 2005;335:124–31.

[5] Hundt W, O’Connell-Rodwell CE, Bednarski MD, Steinbach S, Guccione S. In vitro effect of focused ultrasound or thermal stress on HSP70 expression and cell viability in three tumor cell lines. Acad. Radiol. 2007;14:859–70.

[6] Zhou, Q., Zhu, X., Zhang, J., Xu, Z., Lu, P., & Wu, F. (2008). Changes in Circulating Immunosuppressive Cytokine Levels of Cancer Patients After High Intensity Focused Ultrasound Treatment. Ultrasound in Medicine & Biology, 34(1), 81-87.

[7] Deng J, Zhang Y, Feng J, Wu F. Dendritic cells loaded with ultrasound-ablated tumour induce in vivo specific antitumour immune responses. Ultrasound Med. Biol. 2010;36:441–8.

[8] Hiniker S, Chen D, Knox S. Abscopal Effect in a Patient with Melanoma. N. Engl. J. Med. 2012;366:2035–6.

Click here for additional references from PubMed.

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