Immune cells lose their ‘killer instinct’ in cancer tumors, but their functionality can be reawakened

Some immune cells in our body have their “killer instincts” restricted after entering solid tumors, new research suggests.

In a new article published in Natural communicationsA team led by researchers from the University of Birmingham and the University of Cambridge has discovered how immune cells called natural killer cells (NK cells) rapidly lose their functionality when they enter and reside in tumors.

Using tumor cells cultured from mouse models, the team established that NK cells adopt a dormant state when entering solid tumors due to loss of production of key effector mechanisms used to promote responses. immune systems, including chemokines, cytokines and granzymes. Other studies including cells taken from human colon cancers have confirmed that loss of function of natural killer cells also occurs in humans.

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

David Withers, Professor of Immune Regulation at the University of Birmingham and co-senior author of the study, said: “Natural killer cells are an exciting prospective area in the world of cancer treatment, utilizing the human immune system. body in the fight against the growth of cancer. However, so far we have seen that NK cells have the innate ability to slow cancers, but often appear to lie dormant within tumor cells.

“Using a mouse model, we were able to see specifically what happens to natural killer cells after they enter solid tumor environments, which appears to blunt their killer instinct.

“Importantly, the team also discovered that interleukin-15 treatment could awaken the latent killer instinct in NK cells. This is an extremely exciting finding that allays some of the fears we might have about the behavior of natural killer cells in tumor environments. , and could pave the way for new types of treatments to add to the arsenal to fight solid tumor cancers.

Immune orchestrators stuck in cancers become “exhausted”

In a closely related study also published in Natural communicationsThe research team led by Professors David Withers and Menna Clatworthy also discovered that certain dendritic cells (DCs), immune cells that play a key role in orchestrating the anti-tumor immune response, get stuck in cancers.

The normal function of DCs is to capture material from cancer cells and deliver it to lymph nodes where they stimulate anti-tumor immune responses.

The team discovered that instead of circulating to the lymph nodes, some DCs remain in the tumor, where they become “exhausted”, with a reduced ability to stimulate anti-tumor immune responses and upregulation of signals that could even reduce the function of anti-tumor immune cells. .

Identifying why these cells are trapped and how to overcome this alteration of normal DC behavior could potentially boost anti-tumor responses.

Menna Clatworthy, NIHR Research Professor and Professor of Translational Immunology at the University of Cambridge and co-senior author of both studies, said: “We found that exhausted dendritic cells stuck in the tumor were located next to a type of tumor-killing immune cell, CD8 T cells, potentially preventing them from doing their job. Remarkably, these dysfunctional tumor DCs could be revived through clinically used cancer immunotherapy.

“Our work helps us better understand how cancers can disrupt the immune system and, importantly, how we can rescue it to improve anti-cancer immune responses.”