Impact of Natural Killer Cell Licensing Associated With KIR-HLA Genotype On the Recurrence of Hepatocellular Carcinoma After Curative Hepatectomy: Can the KIR-HLA Genotype Be a Selection Criterion for Potential Donors for Liver Transplantation With Adoptive Immunotherapy Using NK Cells Extracted From Liver Allografts?

Abstract

Natural killer (NK) cells possibly play a role in the immune surveillance of hepatocellular carcinoma (HCC). Self-human leukocyte antigen (HLA) recognition through killer immunoglobulin-like receptors (KIR) confers competence on the NK cells, a process termed licensing. By analyzing the genotypes of the KIR and their HLA ligands with sequence-specific polymorphism-PCR-based typing, we investigated the impact of NK cell licensing on the recurrence of HCC among 170 patients who underwent primary curative hepatectomy using propensity score matching analysis. The presence of each of the functional compound KIR-HLA genotypes, namely, KIR2DL1-C2, KIR2DL2-C1, KIR2DL3-C1, KIR3DL1-Bw4, or KIR3DL2-A3/11,which theoretically license NK cells, did not remarkably influence HCC recurrence. However, the multiplicity of these compound genotypes significantly stratified the HCC recurrence rate after curative hepatectomy, i.e., the cumulative risk of recurrence in patients carrying 3 or more compound genotypes (highly licensing genotypes, n = 46) was significantly lower than that in patients carrying up to 2 compound genotypes (poorly licensing genotypes, n = 92) (1-to-2 matched study, P = 0.0183, adjusted HR= 0.57). This finding indicates that the impact of NK cell licensing on HCC recurrence is a quantitative event. In a separate phase I trial, we successfully performed adoptive immunotherapy by using IL-2-activated NK cells extracted from liver allograft perfusate following living donor liver transplantation (LT) for 20 patients with liver cirrhosis and HCC exceeding stage II. For the patients in this cohort, we also analyzed whether the KIR-HLA genotypes of the recipients/donors influence post-transplant HCC recurrence. When the recipients were treated with NK cells from KIR-HLA-mismatched donors with highly licensing genotypes, in which the inoculated NK cells potentially display their abilities without inhibition from the host HLA ligand, none experienced recurrence within the first 3 years of LT (n = 4). However, 4 of the remaining 16 patients experienced recurrence. This finding could be a promising starting point for further prospective studies to address whether the KIR-HLA genotype is a selection criterion for potential donors for LT with NK cell therapy for HCC.