High-Intensity Focused Ultrasound (HIFU) Triggers Immune Sensitization of Refractory Murine Neuroblastoma to Checkpoint Inhibitor Therapy
Eranki, Avinash; Srinivasan, Priya; Ries, Mario; Kim, AeRang; Lazarski, Christopher A; Rossi, Christopher T; Khokhlova, Tatiana D; Wilson, Emmanuel; Knoblach, Susan M; Sharma, Karun V; Wood, Bradford J; Moonen, Chrit; Sandler, Anthony D; Kim, Peter C W
(2020) Clinical Cancer Research, volume 26, issue 5, pp. 1152 - 1161
(Article)
Abstract
Purpose: Immunotherapy promises unprecedented benefits to patients with cancer. However, the majority of cancer types, including high-risk neuroblastoma, remain immunologically unresponsive. High-intensity focused ultrasound (HIFU) is a noninvasive technique that can mechanically fractionate tumors, transforming immunologically ''cold'' tumors into responsive ''hot'' tumors. Experimental Design: We treated <2% of tumor volume
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in previously unresponsive, large, refractory murine neuroblastoma tumors with mechanical HIFU and assessed systemic immune response using flow cytometry, ELISA, and gene sequencing. In addition, we combined this treatment with aCTLA-4 and aPD-L1 to study its effect on the immune response and long-term survival. Results: Combining HIFU with aCTLA-4 and aPD-L1 significantly enhances antitumor response, improving survival from 0% to 62.5%. HIFU alone causes upregulation of splenic and lymph node NK cells and circulating IL2, IFNg, and DAMPs, whereas immune regulators like CD4 þFoxp3 þ, IL10, and VEGF-A are significantly reduced. HIFU combined with checkpoint inhibitors induced significant increases in intratumoral CD4 þ, CD8a þ, and CD8a þCD11c þ cells, CD11c þ in regional lymph nodes, and decrease in circulating IL10 compared with untreated group. We also report significant abscopal effect following unilateral treatment of mice with large, established bilateral tumors using HIFU and checkpoint inhibitors compared with tumors treated with HIFU or checkpoint inhibitors alone (61.1% survival, P < 0.0001). This combination treatment significantly also induces CD4 þCD44 þhiCD62L þlow and CD8a þCD44 þhiCD62L þlow population and is adoptively transferable, imparting immunity, slowing subsequent de novo tumor engraftment. Conclusions: Mechanical fractionation of tumors using HIFU can effectively induce immune sensitization in a previously unresponsive murine neuroblastoma model and promises a novel yet efficacious immunoadjuvant modality to overcome therapeutic resistance.
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Keywords: Oncology, Cancer Research, Journal Article
ISSN: 1078-0432
Publisher: American Association for Cancer Research Inc.
Note: Funding Information: The authors thank Karuna Panchapakesan, Dr. Surajit Bhattacharya, Mousumi Basu, and Dr. Xiaofang Wu for their assistance in sample preparation and assistance. They also thank Dr. Navid Farr and Dr. Ari Partanen for comments and suggestions regarding HIFU and Dr. Stefan Neirkens and Dr. Luca Gattinoni for help in manuscript development. The authors also acknowledge the support of the CRI Bioinformatics Unit, a partnership between Children's Research Institute (CRI), Center for Genetic Medicine Research, Clinical Translational Science Institute at Children's National (CTSI-CN), and District of Columbia Intellectual and Developmental Disabilities Research Center (DC-IDDRC). This research was supported in part by Sheikh Zayed Institute for Pediatric Surgical Innovation, Joseph E. Robert, Jr. Center for Surgical Care and Board of Visitors at Children's National Health System. This work was also supported in part by Center for Interventional Oncology and Intramural Research Program of the NIH, NIH and National Cancer Institute grants ZID# BC011242 & CL040015, and the NIH-NCI grant 1U01CA202947-01A1. Funding Information: B.J. Wood reports receiving commercial research grants from Philips, Siemens, Celsion Corp, Profound Medical, Exact Robotics, NVIDIA, Biocompatibles BTG, Boston Scientific, and Exact Imaging, and other commercial research support from Philips. P.C.W. Kim is an employee/paid consultant for Activ Surgical Inc. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: © 2020 American Association for Cancer Research Inc.. All rights reserved.
(Peer reviewed)