RESUMO
BACKGROUND & AIMS: Bile duct tumors are rare and have poor prognoses. Natural killer (NK) cells are frequent in human liver and infiltrate these tumors but do not control their progression. Responses of NK cells are regulated by NK immunoglobulin-like receptors (KIRs), which interact with HLA class I ligands. We aimed to characterize the features of the KIR gene loci and their ligands in patients with bile duct cancer (BDC). METHODS: We performed combined multidimensional characterization of genes that encode KIRs and their ligands in blood samples from patients with BDC from Sweden, followed for up to 8 years after diagnosis (n = 148), in 2 geographically matched cohorts of healthy individuals from Northern Europe (n = 204 and n = 900), and in healthy individuals from 6 geographically unrelated populations (n = 2917). We used real-time polymerase chain reaction, RNA sequencing, immunohistochemistry, and flow cytometry to evaluate NK-cell presence, as well as KIR and KIR-ligand expression in bile duct tumors and control tissues. RESULTS: Patients with bile duct tumors had multiple alterations at the KIR gene loci. KIR loci are grouped into genotypes that encode more inhibitory (group A) and more activating (group B) receptors, which can be subdivided into centromeric and telomeric fragments. Patients with BDC had a lower prevalence of KIR2DL3, which was linked to disequilibrium in centromeric A/B and B/B genotypes, compared with control individuals. The associations between KIRs and KIR ligands differed between patients with BDC and control individuals; patients had an altered balance between activating and inhibitory KIRs. KIR-positive NK cells infiltrated biliary tumors that expressed matched KIR ligands. CONCLUSIONS: In a multidimensional analysis of DNA from blood samples of patients with BDC in Europe, we found patients to have multiple alterations at the KIR and HLA gene loci compared with control individuals. These alterations might affect NK-cell tumor surveillance. NK cells from bile duct tumors expressed KIRs and were found in tumors that expressed cognate ligands. This should be considered in development of immune-based therapies for BDC.
Assuntos
Neoplasias dos Ductos Biliares/genética , Antígenos HLA/genética , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Receptores KIR/genética , Idoso , Idoso de 80 Anos ou mais , Ásia , Neoplasias dos Ductos Biliares/sangue , Neoplasias dos Ductos Biliares/imunologia , Neoplasias dos Ductos Biliares/patologia , Estudos de Casos e Controles , Europa (Continente) , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Antígenos HLA/sangue , Antígenos HLA/imunologia , Humanos , Células Matadoras Naturais/patologia , Ligantes , Desequilíbrio de Ligação , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , América do Norte , Fenótipo , Prognóstico , Receptores KIR/sangue , Receptores KIR/imunologia , Receptores KIR2DL3/genética , Receptores KIR2DL3/imunologia , Fatores de Risco , América do Sul , Fatores de TempoRESUMO
INTRODUCTION: Primary sclerosing cholangitis (PSC) is an idiopathic hepatobiliary disorder associated with an increased risk for cholangiocarcinoma (CCA) and a median survival time of 12 years. Reliable predictors of CCA and other major adverse events in PSC are currently lacking. Recently, serum IgE was found to be associated with CCA in a Japanese cohort of PSC patients. Our aim in this study was to determine whether IgE levels predict time to CCA, liver transplantation, or death in a Western (USA-based) cohort of PSC patients. MATERIAL AND METHODS: Thirty-eight patients with PSC and IgE levels were identified and categorized into low or high IgE groups based on the sample median. Groups were compared with respect to clinical characteristics and adverse endpoint-free survival, and the association between IgE and endpoints was assessed with multivariate proportional-hazards models. RESULTS: The median sample age at PSC diagnosis was 41 years, and median serum IgE level was 47.6 kU/L. Low and high IgE groups differed significantly only with respect to IgG subclasses, which were higher among the latter (p < 0.05). There were no significant differences in composite endpoint-free (p = 0.83) or CCA-free survival (p = 0.20). In multivariate analyses, only Mayo PSC risk score and MELD score were significant predictors of endpoint-free survival (p < 0.05). CONCLUSIONS: Serum IgE level is associated with several IgG subclass levels but not time to CCA, liver transplantation, or death among PSC patients in a USA-based cohort. While Mayo PSC risk score and MELD score can predict these outcomes, more specific predictors of CCA are needed.