Some cells of our immune system have their “killer instinct” curtailed after entering solid tumors, new research shows. Researchers from the University of Birmingham and the University of Cambridge have discovered how natural killer (NK) cells in mice lose their function when they enter and settle in tumors.
Their findings are detailed in an article titled ‘Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity,’ published in Nature Communications. Using tumor cells grown from mouse models, the team observed that NK cells enter a dormant state within solid tumors, marked by the loss of production of key effector mechanisms that promote immune responses, including chemokines, cytokines, and granzymes. Further investigations, including cells from human colon cancers, revealed that this loss of function in natural killer cells is also observed in humans.
To test whether the loss of function in NK cells within tumor environments could be reversed, the researchers targeted the IL-15 pathway, currently under trial in patients. This intervention resulted in significantly increased NK cell activity and improved tumor control in the mouse models.
Professor David Withers, PhD, from the University of Birmingham and co-lead author of the study, commented, ‘Natural killer cells are an exciting prospect in the field of cancer treatment, harnessing the body’s immune system to combat cancer growth. However, we’ve observed that NK cells, despite their innate capacity to slow cancers, often become dormant within tumor cells. Through a mouse model, we have been able to observe the specific changes that occur in natural killer cells after entering solid tumor environments, blunting their killer instinct.’
He added, ‘Crucially, the team discovered that treating with Interleukin-15 could re-awaken the dormant killer instinct in NK cells. This is a highly promising discovery that addresses concerns about the behavior of natural killer cells in tumor environments, potentially paving the way for new types of treatment against solid tumor cancers.’
In a closely related study also published in Nature Communications, the research team led by Withers and Professor Menna Clatworthy, FMedSci FLSW, of the University of Cambridge, found that some dendritic cells (DCs), immune cells playing a crucial role in orchestrating anti-tumor immune responses, become stuck within cancers.
The normal function of DCs is to capture material from cancer cells and deliver it to lymph nodes, stimulating anti-tumor immune responses. The team discovered that some DCs, instead of trafficking to lymph nodes, remain within the tumor, where they become ‘exhausted,’ with reduced ability to stimulate anti-tumor immune responses and an upregulation of cues that could potentially reduce the function of anti-tumor immune cells.
Co-lead author Professor Menna Clatworthy stated, ‘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 impeding their function. Remarkably, these dysfunctional tumor DCs could be revived using a cancer immunotherapy currently used in clinics. Our work enhances our understanding of how cancers disrupt the immune system and, crucially, how we can intervene to improve anti-cancer immune responses.'”
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Targeting Interleukin-15 Could Reawaken Dormant NK Cells in Tumors
