Study reveals “dormancy” of natural killer cells in tumors

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According to new research, some of our body’s immune cells find their ‘killer instinct’ curtailed after entering a solid tumor.

In a new paper published Nature communicationA team led by researchers from the University of Birmingham and the University of Cambridge has looked at how immune cells called natural killer cells (NK cells) rapidly lose their function when they enter and reside in tumours.

Using tumor cells grown from mouse models, the team established that NK cells adopt a dormant state when infiltrating solid tumors by losing production of key effector mechanisms used to promote immune responses, including chemokines, cytokines and granzymes. Further studies, including cells taken from human colon cancer, confirmed that loss of natural killer cell function also occurs in humans.

The team also tested whether the loss of function experienced by NK cells could be reversed upon exposure to the future environment. Targeting the IL-15 pathway, which is currently being tested in patients, results in significantly greater NK cell activity and, in mouse models, better tumor control.

Natural killer cells are a promising field in the world of cancer treatment, using the body’s own immune system to fight cancer growth. Until now, however, we have seen that NK cells have an innate ability to slow down cancer but often seem to lie dormant within tumor cells. Using a mouse model, we were able to specifically see what happens to natural killer cells after entering the solid tumor environment—which apparently blunts their killer instincts.”


Importantly, the team also found that treatment with interleukin-15 could reawaken the dormant killer instinct in NK cells. This is a very exciting discovery that addresses some of our fears about how natural killer cells behave in the tumor environment and may pave the way for new types of treatments to add to the arsenal to combat solid tumor cancers.”


David Withers, professor at the University of Birmingham and co-lead author of the study

Immune orchestrators stuck in cancer are “exhausted.”

A closely related study is also published Nature communicationThe research team, led by Professor David Withers and Professor Mena Clatworthy, also found that some dendritic cells (DC), immune cells that play a key role in the anti-tumour immune response, get stuck in the cancer.

The normal function of DC is to capture material from cancer cells and deliver it to lymph nodes where they stimulate the anti-tumor immune system. The team discovered that instead of being trafficked to lymph nodes, some DCs remain in the tumor, where they become “exhausted,” losing their ability to stimulate anti-tumor immunity and upregulating signals that can reduce the effectiveness of anti-tumor cells. .. Identifying why these cells become stuck and how to overcome this impairment of normal DC behavior may enhance anti-tumor responses.

Mena Clatworthy, NIHR Research Professor and Professor of Translational Immunology at the University of Cambridge and co-lead author of the two studies, said:

“We found that exhausted dendritic cells trapped in tumors are located next to a type of tumor killer immune cell, CD8 T cells, potentially preventing them from functioning. Remarkably, these dysfunctional tumor DCs can be revived using cancer immunotherapy. “Clinic. Our work helps us develop our understanding of how cancer can disrupt the immune system and, importantly, how we can rescue it to improve anticancer immunity.”

Source:

Journal Reference:

Dean, I., etc. (2024). Rapid functional impairment of natural killer cells after tumor entry limits anti-tumor immunity. Nature communication. doi.org/10.1038/s41467-024-44789-z.



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