Non-thermal histotripsy tumor ablation promotes abscopal immune responses that enhance cancer immunotherapy

作者：Shibin Qu, Tejaswi Worlikar, Amy E. Felsted, Anutosh Ganguly, Megan Beems, Ryan Hubbard, Ashley Pepple, Alicia A Kevelin, Hannah Garavaglia, Joe Dib, M.S. Toma, Hai Huang, Allan Tsung, Zhen Xu, Clifford Suhyun Cho · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2020 · DOI：10.1136/jitc-2019-000200 · 被引用次数：229 · 研究领域：Ultrasound and Hyperthermia Applications、Cancer Research and Treatments、Cancer Immunotherapy and Biomarkers

BACKGROUND: Developing the ability to use tumor-directed therapies to trigger potentially therapeutic immune responses against cancer antigens remains a high priority for cancer immunotherapy. We hypothesized that histotripsy, a novel non-invasive, non-thermal ablation modality that uses ultrasound-generated acoustic cavitation to disrupt tissues, could engender adaptive immune responses to tumor antigens. METHODS: Immunocompetent C57BL/6 mice inoculated with flank melanoma or hepatocellular carcinoma tumors were treated with histotripsy, thermal ablation, radiation therapy, or cytotoxic T lymphocyte-associated protein-4 (CTLA-4) blockade checkpoint inhibition. Lymphocyte responses were measured using flow cytometric and immunohistochemical analyses. The impact of histotripsy on abscopal immune responses was assessed in mice bearing bilateral tumors, or unilateral tumors with pulmonary tumors established via tail vein injection. RESULTS: Histotripsy ablation of subcutaneous murine melanoma tumors stimulated potent local intratumoral infiltration of innate and adaptive immune cell populations. The magnitude of this immunostimulation was stronger than that seen with tumor irradiation or thermal ablation. Histotripsy also promoted abscopal immune responses at untreated tumor sites and inhibited growth of pulmonary metastases. Histotripsy was capable of releasing tumor antigens with retained immunogenicity, and this immunostimulatory effect was associated with calreticulin transl...