Study reveals ‘dormancy’ of natural killer cells in tumors

Some immune system cells in our bodies see their ‘killer instinct’ curtailed after entering solid tumors, according to new research.

In a new paper published in Nature communicationsa team led by researchers from the University of Birmingham and the University of Cambridge discovered how immune cells called natural killer cells (NK cells) quickly lose their functionality when they enter and reside in tumors.

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

The team further investigated whether the loss of function experienced by NK cells upon entry into tumor environments could be reversed. Targeting the IL-15 pathway, which is currently being tested in patients, resulted in significantly greater NK cell activity and in mouse models better tumor control.

Natural killer cells are an exciting prospect 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 the innate ability to slow down cancers, but often seem to lie dormant within the cancer cells. “Using a mouse model, we were able to see specifically what happens to natural killer cells after they enter solid tumor environments – which apparently blunts their killer instinct.”

Crucially, the team also discovered that treatment with Interleukin-15 could reawaken the dormant killer instinct in NK cells. This is an extremely exciting discovery that allays some of the fears we may have about how natural killer cells behave in tumor environments and could pave the way for new types of therapy to be added to the arsenal for treating solid tumors ».

David Withers, a professor at the University of Birmingham and co-leader of the study

Immune orchestrators stuck in cancers ‘run out’

In a closely related study also published in Nature communicationsthe research team led by Professor David Withers and Professor Menna Clatworthy also found that some dendritic cells (DCs), immune cells that play a key role in orchestrating the anti-tumor immune response, stick to cancers.

The normal function of DCs is to capture material from tumor cells and deliver it to lymph nodes where they stimulate antitumor immune responses. The team discovered that instead of trafficking to lymph nodes, some DCs remain in the tumor, where they become “exhausted”, with a reduced ability to stimulate anti-tumor immune responses and up-regulation of signals that could even reduce the function of anti-tumor immune cells. Identifying why these cells become trapped and how to overcome this disruption of normal DC behavior has the potential to enhance antitumor responses.

Menna 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 the depleted dendritic cells that had stuck to the tumor were adjacent to a type of tumor-killing immune cell, the CD8 T cells, potentially preventing them from doing their job. Remarkably, these dysfunctional tumor DCs could be revived using a cancer immunotherapy used in the clinic. The work helps us understand how cancers can disrupt the immune system and, crucially, how we can rescue it to improve anti-tumor immune responses.”