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KIR-HLA System Gene Loci Imbalance and Biliary Tract Cancer

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Key Points

  • The analysis revealed multiple layers of imbalance in the KIR-HLA system and an increased frequency of rare combinations of natural killer immunoglobulin-like receptors (KIRs) in patients with biliary tract cancer.
  • As compared to geographically matched populations, patients with biliary tract cancer appeared to have different associations between the activating and inhibitory KIR genes.
  • Researchers also showed that NK cells expressing KIRs infiltrate the actual tumors of these patients.

Patients with biliary tract cancer have an altered genetic architecture in some immune system receptor systems, according to research published by Cornillet et al in Gastroenterology.

Research Findings

Researchers at Karolinska Institutet investigated the genetic architecture of two large genetic clusters encoding immune system receptors, the KIR-HLA system, which controls the function of natural killer (NK) cells. The two families of genes that make up the KIR-HLA system are among the most complex gene families in the human genome, which has made it difficult to map their genetic composition.

“We found that the genetic architecture of the KIR-HLA system is in imbalance in patients with biliary tract cancer. These results provide a theoretical framework for future targeted immunotherapy design focused on these receptors,” said Niklas Björkström, MD, PhD, physician and researcher in the Karolinska Institutet’s Department of Medicine.

“One of the most important functions of NK cells is to eliminate cancer, and many previous researchers have found links between the KIR-HLA system and risk for cancer,” explained Dr. Björkström. “Based on this, there are now treatments in clinical trials aimed at altering the function of NK cells by targeting receptors on the cell surface.”

To study the full complexity of the genetic architecture of the KIR-HLA system, researchers performed sequencing of these gene families and developed a number of new tools to analyze, depict, and interpret the studied gene families. These tools were subsequently used on a prospective cohort of 148 patients with biliary tract cancer and compared with two geographically matched and six nongeographically matched control populations.

“Our analysis revealed multiple layer[s] of imbalance in the KIR-HLA system and an increased frequency of rare combinations of natural killer immunoglobulin-like receptors (KIRs) in patients with biliary tract cancer,” said first study author Martin Cornillet, PhD, of the Karolinska Institutet’s Department of Medicine. “As compared to geographically matched populations, the patients appeared to have different associations between the activating and inhibitory KIR genes. We also managed to show that NK cells expressing KIRs infiltrate the actual tumors of these patients.”

The researchers concluded, “In a multi-dimensional analysis of DNA from blood samples of patients with bile duct cancer 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 bile duct cancer.”

Disclosure: The research was funded by the Swedish Research Council, the Swedish Cancer Society, the Swedish Foundation for Strategic Research, the Swedish Society for Medical Research, the Cancer Research Foundations of Radiumhemmet, Knut and Alice Wallenberg Foundation, the Novo Nordisk Foundation, the Center for Innovative Medicine at Karolinska Institutet, the Stockholm County Council, Karolinska Institutet, the Research Council of Norway, and the Norwegian Cancer Foundation and the KG Jebsen Foundation. For full disclosures of the study authors, visit gastrojournal.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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