Immune cells lose ’killer instinct’ in cancerous tumours - but functionality can be re-awakened

Colorized scanning electron micrograph of a natural killer cell from a human don
Colorized scanning electron micrograph of a natural killer cell from a human donor, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, CC BY-NC 2.0 DEED
First study tracking how NK cells respond in tumours found that stimulating the IL-15 pathway prevented the rapid loss of function and improved tumour control

Some immune cells in our bodies see their ’killer instinct’ restricted after entering solid tumours, according to new research.

In a new paper published in Nature Communications , a team led by researchers from the University of Birmingham and the University of Cambridge found how immune cells called natural killer cells (NK cells) rapidly lose their functionality when entering and residing in tumours.

Using tumour cells grown from mice models, the team established that NK cells adopt a dormant state when entering solid tumours through the loss of production of key effector mechanisms used to promote immune responses including chemokines, cytokines, and granzymes. Further studies including cells taken from human colon cancers confirmed that the loss of function of natural killer cells happens in people too.

The hugely exciting discovery.... could pave the way for new types of treatment to add to the arsenal to tackle solid tumour cancers

Professor David Withers

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

David Withers, Professor of Immune Regulation at the University of Birmingham and co-lead author of the study said:

"Natural killer cells are an exciting prospective field in the world of cancer treatment, using the body’s own immune system in the fight against cancer growth. Up until now though, we have seen that NK cells have the innate capacity to slow cancers but often seem to lie dormant within tumour cells. Using a mice model, we have been able to specifically see what happens to Natural killer cells after entering solid tumour environments - which seemingly blunts their killer instinct."

"Crucially, the team also found that treating with Interleukin-15 could re-awaken the dormant killer instinct in the NK cells. This is a hugely exciting discovery that allays some of the fears we may have about how natural killer cells behave in tumour environments, and could pave the way for new types of treatment to add to the arsenal to tackle solid tumour cancers."

Immune orchestrators stuck in cancers become "exhausted"

In a closely related study also published in Nature Communications , the research team led by Professor David Withers and Professor Menna Clatworthy also found that some dendritic cells (DCs), immune cell that play a key role in orchestrating anti-tumour immune response, get stuck within cancers.

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

The team discovered that rather than trafficking to lymph nodes, some DCs stay in the tumour, where they become "exhausted", with reduced ability to stimulate anti-tumour immune responses, and upregulation of cues that could even reduce anti-tumour immune cell function.

Identifying why these cells become trapped and how to overcome this impairment to normal DC behaviour has the potential to boost anti-tumour 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 exhausted dendritic cells stuck in the tumour were located next to a type of tumour killer immune cell, CD8 T cells, potentially preventing them from doing their job. Remarkably, these dysfunctional tumour DCs could be revived using a cancer immunotherapy that’s used in the clinic.

"Our work helps develop our understanding of how cancers can disrupt the immune system, and crucially, how we can rescue this to improve anti-cancer immune responses."

    For media enquiries please contact Tim Mayo , Press Office, University of Birmingham, 7815 607157.

    The University of Birmingham is ranked amongst the world’s top 100 institutions. Its work brings people from across the world to Birmingham, including researchers, teachers and more than 8,000 international students from over 150 countries.

    The University of Birmingham is a founding member of Birmingham Health Partners (BHP), a strategic alliance which transcends organisational boundaries to rapidly translate healthcare research findings into new diagnostics, drugs and devices for patients. Birmingham Health Partners is a strategic alliance between seven organisations who collaborate to bring healthcare innovations through to clinical application:
    • University of Birmingham
    • University Hospitals Birmingham NHS Foundation Trust
    • Birmingham Women’s and Children’s Hospitals NHS Foundation Trust
    • Aston University
    • The Royal Orthopaedic Hospital NHS Foundation Trust
    • Sandwell and West Birmingham Hospitals NHS Trust
    • West Midlands Academic Health Science Network
    • Birmingham and Solihull Mental Health NHS Foundation Trust

    Full citations: Dean, I., Lee, C.Y.C., Tuong, Z.K. et al. Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity. Nat Commun 15, 683 (2024).­’024 -44789-z

    Lee, C.Y.C., Kennedy, B.C., Richoz, N. et al. Tumour-retained activated CCR7+ dendritic cells are heterogeneous and regulate local anti-tumour cytolytic activity. Nat Commun 15, 682 (2024).­’024 -44787-1

Experimental cancer therapy research continues at Birmingham

New and innovative ways to detect and treat cancer being trialled at Birmingham are to receive renewed funding from Cancer Research UK and the NIHR.