Genetic imbalance in the immune system can lead to bile duct cancer

Disease and treatment 6. sep 2019 4 min Group Leader, MD PhD, Associate Professor Niklas Björkström Written by Kristian Sjøgren

People with bile duct cancer or gallbladder cancer are often predisposed to genetic changes that make the immune system unable to kill the cancer cells. The discovery may lead to better diagnosis and treatment of people with these rare types of cancer.

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New research led by Swedish researchers reveals that bile duct and gallbladder cancer often result from changes in the genetics of natural killer cells in the immune system.

When genes are altered, the immune system cannot recognize the cancer cells in the bile duct and the gallbladder as well as previously, and if the immune system does not eliminate these cancer cells in the early stages of the disease, the cancer can become very severe.

Fortunately, the new research findings also suggest how the discovery can be used to diagnose people with bile duct cancer earlier and how immunotherapy could be used to cure these people.

“Our results show that people with bile duct cancer have an imbalance in the ability of the immune system to recognize specific proteins on the surface of the cancer cells. Our results thus comprise the theoretical framework for developing immunotherapy to target these proteins,” explains a main author, Niklas Björkström, Associate Professor, Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

The new research results were recently published in Gastroenterology.

Immunotherapy has revolutionized cancer treatment

Immunotherapy has revolutionized cancer treatment within the past decade. It is almost magically capable of curing types of cancer that previously killed people.

The discovery of the basis for developing immunotherapy was recognized through a Nobel Prize in Physiology or Medicine in 2018. Immunotherapy basically means that the immune system already has all the necessary tools to manage the presence of cancer cells.

The immune system eliminates cells if it discovers that a cell does not look or behave like cells normally should. The immune system achieves this through its many killer cells seeking and recognizing proteins on the surface of cancer cells. If the immune system cells find such a protein, they kill the cancer cell.

However, cancer often develops anyway because cancer cells on the cell surface express some proteins that downregulate the immune response, so that the immune cells leave them alone.

Immunotherapy for treating this form of cancer comprises molecules that inhibit these proteins, thereby enabling the immune system to function correctly.

Cancer can also develop if there is a genetic mismatch between the proteins on the surface of cancer cells and the proteins on the immune system cells that recognize them. A deficiency in the ability of the immune system to recognize cancer cells underlies the genetic predisposition for developing cancer.

“Until recently, we thought that once cancer develops, the immune system has lost the battle against the cancer cells and nothing more can be done. However, research over the past decade has shown that targeting specific interactions between the immune system and the cancer cells can reactivate the immune system’s ability to attack the cancer cells. Naturally, this has meant that many researchers are now studying the precise interactions between cancer cells and the immune system in various types of cancer. We hope that immunotherapy can reactivate these interactions that can help to combat cancer,” explains Niklas Björkström.

Researchers map how the immune system combats bile duct cancer

The researchers from Karolinska Institutet have mapped out how the immune system recognizes cancer cells in the bile ducts and how the process goes wrong when cancer appears.

The KIR-HLA (natural-killer cell immunoglobulin-like receptor–human leukocyte antigen) system plays a role when bile duct cancer and gallbladder cancer develop.

The KIR-HLA system controls the immune system’s killer cells, and KIR is the protein on the natural killer cells used to recognize HLA on cancer cells in the bile duct.

If the natural killer cells encounter a cancer cell that expresses HLA, they kill the cancer cell.

However, the KIR-HLA system may become genetically imbalanced, and then the natural killer cells cannot recognize the cancer cells, which then grow uncontrollably.

That is exactly what the new research results show.

“In our research, we have found multiple layers of disequilibrium in the KIR-HLA system that may help to explain why some people develop bile duct cancer. This also suggests that the risk of developing bile duct cancer is largely innate,” says Niklas Björkström.

People with bile duct cancer have genetic predisposition

Niklas Björkström and colleagues have developed various genetic tools to map the genetic structure underlying the KIR-HLA system.

The KIR-HLA system is based on several genes that are some of the most complex in the human genome. This also explains why no one has been able to complete this analysis until now.

After mapping the KIR-HLA system, the researchers used their tools to investigate the genetics of 148 people with bile duct cancer and almost 900 controls.

They found several genetic differences between the people who developed bile duct cancer and those who did not.

They also directly saw how natural killer cells that properly express KIR are capable of infiltrating tumours.

“People who develop bile duct cancer have more variation in the KIR genes, which means that their natural killer cells are not fully optimized to recognize and eradicate cancer in the early stages. However, when the natural killer cells express KIR correctly, they are able to fight the cancer,” says Niklas Björkström.

Can be used in both treatment and diagnosis

The new research results highlight several possibilities in improving the perspectives of people who develop bile duct cancer.

Bile duct cancer is difficult to treat because it is a rare form of cancer and is often discovered at a late stage because the symptoms only arise when it is almost too late to do anything.

The 5-year survival rate for people with bile duct cancer is therefore less than 10%.

The new research results, however, might make it easier to identify individuals who are predisposed to developing bile duct cancer. It is literally written in their genes that their natural killer cells are not equipped with the best ammunition to find and kill the cancer cells that develop in their bile ducts.

Second, the mechanistic understanding of the KIR-HLA system and the faults in the system that can lead to bile duct cancer provide more opportunities for researchers to design immunotherapy that can help people.

“Clinical trials are already being conducted in an attempt to target KIR so that the natural killer cells become more active. The results of these trials will be exciting. In addition, clinical collaborators at our hospital are conducting a trial following 700 people at high risk of developing bile duct cancer and examining whether we can predict who ends up developing the disease and how early in the process we can discover it,” says Niklas Björkström.

Imbalance of genes encoding natural killer immunoglobulin-like receptors and human leukocyte antigen in patients with biliary cancer” has been published in Gastroenterology. In 2014, the Novo Nordisk Foundation awarded a grant to Niklas Björkström for the project Role for Natural Killer (NK) Cell-mediated Hepatic Inflammation in Progression from Obesity-induced NAFLD to NASH.

Our group performs translational immunological research studying tissue-resident natural killer cells in the human liver and uterus. Björkström Rese...

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