{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T04:39:08Z","timestamp":1782275948406,"version":"3.54.5"},"reference-count":39,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2020,10,28]],"date-time":"2020-10-28T00:00:00Z","timestamp":1603843200000},"content-version":"unspecified","delay-in-days":27,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"VA merit Award I01","award":["BX004065-1"],"award-info":[{"award-number":["BX004065-1"]}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA208396"],"award-info":[{"award-number":["R01CA208396"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2020,8,26]]},"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Minimally invasive radiofrequency ablation (RFA) is used as a first-line treatment option for hepatocellular cancer (HCC) with the weaknesses of incomplete ablation, tumor recurrence, and inferior outcomes. To overcome this limitation, we proposed to develop sunitinib-RFA integrated therapy with a potential of activating anti-HCC immune response.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Using our unique murine model, we developed a novel RFA platform with a modified human cardiac RF generator. Therapeutic efficacy of sunitinib\u2013RFA combined treatment in HCC was tested in this platform. Tumor progression was monitored by MRI; tumor necrosis and apoptosis were detected by H&amp;E and terminal deoxynucleotidyl transferase dUTP nick end labeling; immune reaction was defined by flow cytometry; and signaling molecules were examined with real-time PCR (qPCR), western blot, and immunohistochemical staining.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>A significantly reduced tumor growth and extended lift span were observed in the mice receiving combined treatment with RFA and sunitinib. This combined treatment significantly increased the frequency of CD8<jats:sup>+<\/jats:sup> T cell, memory CD8<jats:sup>+<\/jats:sup> T cell, and dendritic cells (DCs); decreased the frequency of regulatory T cells; and activated tumor-specific antigen (TSA) immune response in tumor microenvironment. We found that RFA caused PD-1 upregulation in tumor-infiltrated T cells by boosting hepatocyte growth factor (HGF) expression, which was suppressed by sunitinib treatment. We have also demonstrated that sunitinib suppressed VEGF\u2019s effect in enhancing PD-L1 expression in DCs and attenuated heat-sink effect. The results indicate that RFA induced tumor destruction and release of in situ TSAs which can activate a tumoricidal immune response in sunitinib-treated mice, significantly improving anti-HCC therapeutic efficacy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Sunitinib enables RFA-released in situ TSA to ignite an effective anti-tumor immune response by suppressing HGF and VEGF signaling pathways. Sunitinib\u2013RFA as a synergistic therapeutic approach significantly suppresses HCC growth.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2020-001038","type":"journal-article","created":{"date-parts":[[2020,10,28]],"date-time":"2020-10-28T17:10:26Z","timestamp":1603905026000},"page":"e001038","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":83,"title":["Synergizing sunitinib and radiofrequency ablation to treat hepatocellular cancer by triggering the antitumor immune response"],"prefix":"10.1136","volume":"8","author":[{"given":"Xiaoqiang","family":"Qi","sequence":"first","affiliation":[{"name":"Department of Surgery, University of Missouri, Columbia, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Missouri, Columbia, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixin","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Missouri, Columbia, Missouri, USA"},{"name":"Harry S. Truman Memorial VA Hospital, Columbia, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeline","family":"Sauer","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Missouri, Columbia, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Avella","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Missouri, Columbia, Missouri, USA"},{"name":"Ellis Fischel Cancer Center, University of Missouri, Columbia, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jussuf T","family":"Kaifi","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Missouri, Columbia, Missouri, USA"},{"name":"Ellis Fischel Cancer Center, University of Missouri, Columbia, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Bryan","sequence":"additional","affiliation":[{"name":"Department of Veterinary Oncology, University of Missouri, Columbia, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Cheng","sequence":"additional","affiliation":[{"name":"Pharmacology and Pharmaceutical Sciences, University of Missouri Kansas City, Kansas City, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin F","family":"Staveley-O\u2019Carroll","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Missouri, Columbia, Missouri, USA"},{"name":"Harry S. 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