高强度热应激增强过继性 NK 细胞对低分化肝细胞癌的细胞毒性

Percutaneous thermal ablation is used to treat early-stage, non-resectable hepatocellular carcinoma (HCC). NK-cell immunotherapy has been studied as an adjuvant treatment, but the efficacy remains unclear when combined with ablation.

To evaluate the potential of peri-ablational, high-intensity thermal stress to augment adoptive NK-cell cytotoxicity in HCC.

HCC cells were exposed to 37, 43, and 47 C in water baths to recapitulate peri-ablational heat stress before delivering NK-cell therapy. In vitro cytolysis was measured using chromium release and live-cell imaging assays. An orthotopic mouse model of poorly differentiated HCC was used to evaluate the therapeutic effect of combined microwave ablation (MWA) and adoptive NK-cell therapy. Tumor burden was compared via tumor weight, Gaussia luciferase levels, and immunohistochemistry.

NK-cell cytotoxicity increased against poorly differentiated HCC cells pretreated at 47 C compared with 37 C controls ( p < 0.001). In vivo , MWA+NK-cell therapy reduced poorly differentiated HCC weight (1.53 0.44 g) compared to monotherapy groups (MWA: 2.06 0.61; NK: 1.92 0.75 g), although the difference was only found to be significant when compared to untreated tumor group (2.89 0.92 g, p < 0.01). Additionally, MWA+NK-cell therapy significantly decreased Gaussia luciferase level ( p < 0.05) and Ki-67 expression ( p < 0.01), while increasing tumor necrosis ( p < 0.05) in tumors when compared to tumor control.

High intensity thermal stress increased susceptibility of poorly differentiated HCC to NK-cell-mediated cytotoxicity in vitro and in vivo when compared to untreated controls. The combination of thermal ablation and adoptive NK-cell therapy should be further investigated in clinically relevant sub-lethal ablation settings and broader ablation-time combinations to support future clinical studies.