Authors' Affiliations: Clinical Pathology-Toxicology, Ospedale S. Agostino-Estense, Modena; U.O. Infectious Diseases and Hepatology; U.O. Medical Genetics, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; and Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Department of Laboratory Medicine, Azienda Ospedaliera ASMN, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia, Italy.
Clin Cancer Res. 2013 Oct 1;19(19):5465-73. doi: 10.1158/1078-0432.CCR-13-0986. Epub 2013 Aug 12.
We evaluated the impact of the killer immunoglobulin-like receptors (KIR) of natural killer (NK) cells and of their HLA ligands over the clinical outcome of hepatitis C virus (HCV)-related hepatocellular carcinoma after curative treatment by either surgical resection or radiofrequency thermal ablation (RTA).
Sixty-one consecutive patients with HCV-related hepatocellular carcinoma underwent KIR genotyping and HLA typing. A phenotypic/functional characterization of NK cells was carried out in patients with different KIR/KIR-ligand genotype.
Activating KIR2DS5 was associated with significantly longer time to recurrence (TTR) and overall survival (OS; P < 0.03 each). Homozygous HLA-C1 (P < 0.02) and HLA-Bw4I80 (P < 0.05) were expressed by patients with significantly better OS, whereas HLA-C2 (P < 0.02) and HLA-Bw4T80 (P < 0.01) were associated with a worse OS. Multivariate analysis identified as parameters independently related to TTR the type of treatment (surgical resection vs. RTA; P < 0.03) and HLA-C1 (P < 0.03), whereas only KIR2DS5 was an independent predictor of longer OS (P < 0.05). Compound KIR2DL2-C1 and KIR3DS1-Bw4T80 genotypes were associated with better TTR (P < 0.03) and worse OS (P = 0.02), respectively. A prevalent cytotoxic (CD56(dim)) NK phenotype was detected in patients with both longer TTR and OS. Cytotoxic capacity measured by upregulation of CD107a was significantly higher in subjects with HLA-C1 alone or combined with KIR2DL2/KIR2DL3.
These results support a central role of NK cells in the immune response against hepatocellular carcinoma, providing a strong rationale for therapeutic strategies enhancing NK response and for individualized posttreatment monitoring schemes.
我们评估了自然杀伤 (NK) 细胞杀手免疫球蛋白样受体 (KIR) 及其 HLA 配体对根治性手术切除或射频热消融 (RTA) 治疗后丙型肝炎病毒 (HCV) 相关肝细胞癌临床转归的影响。
61 例连续的 HCV 相关肝细胞癌患者接受了 KIR 基因分型和 HLA 分型。对不同 KIR/KIR 配体基因型患者的 NK 细胞进行表型/功能特征分析。
激活型 KIR2DS5 与复发时间 (TTR) 和总生存时间 (OS) 显著延长相关 (P < 0.03)。纯合 HLA-C1 (P < 0.02) 和 HLA-Bw4I80 (P < 0.05) 的表达与显著延长的 OS 相关，而 HLA-C2 (P < 0.02) 和 HLA-Bw4T80 (P < 0.01) 与 OS 更差相关。多变量分析确定治疗方式 (手术切除与 RTA；P < 0.03) 和 HLA-C1 (P < 0.03) 是与 TTR 独立相关的参数，而只有 KIR2DS5 是 OS 更长的独立预测因子 (P < 0.05)。KIR2DL2-C1 和 KIR3DS1-Bw4T80 复合基因型与 TTR 更长 (P < 0.03) 和 OS 更差 (P = 0.02) 相关。在 TTR 和 OS 均更长的患者中检测到一种常见的细胞毒性 (CD56(dim)) NK 表型。通过 CD107a 上调测量的细胞毒性能力在仅 HLA-C1 或与 KIR2DL2/KIR2DL3 联合的患者中显著更高。
这些结果支持 NK 细胞在针对肝细胞癌的免疫反应中发挥核心作用，为增强 NK 反应的治疗策略和个体化治疗后监测方案提供了强有力的理论依据。
