PT  - JOURNAL ARTICLE
AU  - Xiaoqiang Qi
AU  - Ming Yang
AU  - Lixin Ma
AU  - Madeline Sauer
AU  - Diego Avella
AU  - Jussuf T Kaifi
AU  - Jeffrey Bryan
AU  - Kun Cheng
AU  - Kevin F Staveley-O’Carroll
AU  - Eric T Kimchi
AU  - Guangfu Li
TI  - Synergizing sunitinib and radiofrequency ablation to treat hepatocellular cancer by triggering the antitumor immune response
AID  - 10.1136/jitc-2020-001038
DP  - 2020 Oct 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e001038
VI  - 8
IP  - 2
4099  - http://jitc.bmj.com/content/8/2/e001038.short
4100  - http://jitc.bmj.com/content/8/2/e001038.full
SO  - J Immunother Cancer2020 Oct 01; 8
AB  - Background 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.Methods Using our unique murine model, we developed a novel RFA platform with a modified human cardiac RF generator. Therapeutic efficacy of sunitinib–RFA combined treatment in HCC was tested in this platform. Tumor progression was monitored by MRI; tumor necrosis and apoptosis were detected by H&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.Results 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+ T cell, memory CD8+ 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’s 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.Conclusions Sunitinib enables RFA-released in situ TSA to ignite an effective anti-tumor immune response by suppressing HGF and VEGF signaling pathways. Sunitinib–RFA as a synergistic therapeutic approach significantly suppresses HCC growth.