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Gastroenterology. 2019 Jun 20. pii: S0016-5085(19)41030-5. doi: 10.1053/j.gastro.2019.06.023. [Epub ahead of print]

Imbalance of Genes Encoding Natural Killer Immunoglobulin-like Receptors and Human Leukocyte Antigen in Patients With Biliary Cancer.

Author information

1
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. Electronic address: martin.cornillet.jeannin@ki.se.
2
Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
3
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
4
Center for Biomedical Research, Faculty of Medicine, Autonomous University of Coahuila, Torreon, Mexico.
5
Transplant Immunology Laboratory, Royal Liverpool University Hospital, Liverpool, UK.
6
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway.
7
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. Electronic address: Niklas.bjorkstrom@ki.se.

Abstract

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 natural killer 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 multi-dimensional characterization of genes that encode KIRs and their ligands in blood samples from patients with BDC from Sweden, followed for as long as 8 years after diagnosis (n=148), in 2 geographically matched cohorts of healthy individuals from Northern Europe (controls, n=204 and n=900), and in healthy individuals from 6 geographically unrelated populations (controls, n=2917). We used real-time PCR, RNAseq, 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 controls. The associations between KIRs and KIR ligands differed between patients with BDC and controls; 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 multi-dimensional 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 controls. 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.

KEYWORDS:

cholangiocarcinoma; genetic variant; heterozygote advantage; liver cancer

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