HLA and killer immunoglobulin-like receptor genes as outcome predictors of hepatitis C virus-related hepatocellular carcinoma.
OBJECTIVE
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).


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
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.
Elisabetta
E
Cariani
Massimo
M
Pilli
Alessandro
A
Zerbini
Cristina
C
Rota
Andrea
A
Olivani
Paola
P
Zanelli
Adele
A
Zanetti
Tommaso
T
Trenti
Carlo
C
Ferrari
Gabriele
G
Missale
D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000601:surgery / Q000821:virology; D003602:Cytotoxicity, Immunologic; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D016174:Hepacivirus; D019698:Hepatitis C, Chronic / Q000821:virology; D006650:Histocompatibility Testing; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000601:surgery / Q000821:virology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D054340:Receptors, KIR / Q000235:genetics*; D012008:Recurrence; D016896:Treatment Outcome; D047368:Tumor Burden
D006680:HLA Antigens; D054340:Receptors, KIR; D007371:Interferon-gamma