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Radiofrequency thermal ablation represents an effective treatment for hepatocellular carcinoma (HCC) and it can also exert an “adjuvant” effect on spontaneous antitumor T-cell responses, as suggested by human and animal studies. The adjuvant effect is thought to depend on the huge amount of necrotic tumor antigen made available to the immune system by HCC thermal ablation. In addition, radiofrequency thermal ablation may result in the release of local stimuli responsible for activation and maturation of antigen-presenting cells (APCs). To test this hypothesis, we studied APC maturation and function in 19 patients undergoing thermal ablation for HCC. Patients' monocytes induced to differentiate with granulocyte macrophage colony-stimulating factor (GM-CSF), or GM-CSF plus IL-4, were cocultured in vitro with tumor debris generated by radiofrequency thermal ablation. Expression of costimulatory molecules, lymphnode homing chemokine receptor, antigen presentation, and cytokine secretion were enhanced by incubation with HCC treated tissue as compared with untreated HCC and nontumor liver tissue. Moreover, HCC-specific T-cell responses could be induced by monocytes activated with GM-CSF and incubated with thermally ablated HCC tissue. HCC thermal ablation can create an antigenic source along with stimuli appropriate for maturation of APCs to induce HCC-specific T-cell responses. These results contribute to explain at least in part the adjuvant effect of HCC thermal ablation and suggest a novel strategy to induce maturation of APCs and their loading with HCC antigens for active immunotherapy protocols aimed at reducing HCC recurrence after thermal ablation.