Synergizing sunitinib and radiofrequency ablation to treat hepatocellular cancer by triggering the antitumor immune response

Abstract

BackgroundMinimally 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.MethodsUsing 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.ResultsA 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.ConclusionsSunitinib 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.

Melatonin enhances radiofrequency-induced NK antitumor immunity, causing cancer metabolism reprogramming and inhibition of multiple pulmonary tumor development

“…It was reported that RFA not only destroyed local tumor tissues but also induced antitumor immunity. 10 , 35 Consistently, our results show that RFA significantly increased the infiltration of immune cells including macrophages, DCs and NK cells in non-ablated tumor tissues, and this became more obvious after RFA + MLT treatment. NK cells showed spontaneous cytotoxic activity against tumor cells and released cytokines, which modulate the function of other immune cells, and thus played a key role in tumor immunotherapy.…”

“… 9 Although RFA could induce antitumor immunity, it is still accompanied by high recurrence rates in the treatment of early lung cancer with multiple GGNs. 10 Recently, combinations of local treatments with systemic therapy, such as targeted therapy, chemotherapy, and immunotherapy, have been suggested for reducing lung cancer recurrence and malignancy. 11 – 13 However, these treatments have significant side effects or need proper diagnosis, which makes systemic therapies unsuitable for treating early lung cancer with GGNs.…”

Turning cold tumors into hot tumors by improving T-cell infiltration

“…Inhibition of VEGF by sunitinib also promoted DC activation and inhibited tumor angiogenesis. Combination therapy ultimately led to a remarkable increase in CD8 + T lymphocytes and DCs as well as a decrease in Tregs, thus overcoming the drawbacks of monotherapy 123 . In addition, HIFU, as a new minimally invasive ablation therapy, has become a hotspot of cancer treatment.…”

Astaxanthin Prevents Diet-Induced NASH Progression by Shaping Intrahepatic Immunity

“…The isolation of liver-infiltrating leukocytes has been described in our previous publication [60]. Briefly, liver perfusion was first performed in mice under anesthesia via the portal vein with 0.05% collagenase (Gibco, Gaithersburg, MD, USA) in Ca 2+ -free PBS at a pump speed of 4 mL/min.…”

“…Ex vivo staining of lymphocytes with fluorochrome-labeled antibodies was performed on single-cell suspensions as described [60]. For intracellular staining, the cells were fixed and permeabilized with buffer (ThermoFisher Scientific, Waltham, MA, USA), and stained with fluorochrome-conjugated antibodies.…”