Researchers at the Babraham Institute and the University of Catanzaro "Magna Graecia," Italy, coordinating an international network of scientists and clinicians from Europe, the USA, and Japan, have identified new mechanisms through which the immune system recognizes and responds to tumors like melanomas. This discovery may offer therapeutic approaches for tackling metastatic melanoma, an aggressive form of skin cancer responsible for around 2,000 deaths in the UK each year.
These exciting new findings reveal how a type of white blood cell - Natural Killer (NK) cells - tackles tumors, characterizing for the first time the molecular interactions that lead to melanoma destruction. This has advanced understanding of melanoma recognition by the immune system and has the potential to open up new avenues of research into the prevention of metastasis by harnessing NK cells’ natural immunity.
Natural Killer cells are found in the blood, the lymph glands, and in tissues such as the liver, the lungs, and the uterus, where they participate in immune defenses against infection, cancer, in reproductive success, and in transplantation. They play a key role in the immune response that targets tumor cells, while sparing healthy cells; mouse models revealed that NK cells prevent and control tumor growth although, in the case of melanomas, the molecular interactions behind this and how NK cells control metastatic progression had until now remained elusive.
The team of researchers, led by Francesco Colucci (pictured), Group Leader at the Babraham Institute, and Ennio Carbone, of the University of Catanzaro "Magna Graecia," Italy, studied both human metastatic melanomas - aggressive forms of skin cancer that have spread to other sites - and spontaneous mouse melanomas.
NK cells sense signs of infection and recognize abnormal cells, including tumors and their metastases, via receptors on their cell membrane. One such family is natural cytotoxicity receptors (NCRs), which act like cancer-detection antennae seeking out molecules associated with tumors. Two receptors have been identified that are critical for NK cell-mediated killing of melanoma cells. Using cell lines from 18 melanoma patients, the team found that melanoma cell lines produce proteins that bind to natural cytotoxicity receptors (NCRs) and a receptor that activates NK cells called DNAX accessory molecule-1 (DNAM-1). These cell lines were susceptible to being destroyed by NK cells both in vitro and after being transplanted into mice. Consistent with these data from human cell lines, mouse spontaneous melanomas and melanoma cell lines also produced proteins that bind to DNAM-1 and NCRs.
“Interfering with the ability of DNAM-1 and NCRs to interact with proteins on melanoma cells, by either genetic means or by antibody-blockade, reduced NK cell-mediated killing of human and mouse melanoma cells lines both in vitro and in vivo,” explained Dr Francesco Colucci. “Informed by these findings, we explored the potential of NK cells in cell therapy of melanoma in “humanized” mice, which is a standard method to understand how human cells work in the whole organism. The results strikingly showed that human NK cells were able to prevent death of the mice by killing the transplanted human melanoma cells.”
He added, “We are now setting up the next stage of the research program. DNAM-1 and NCRs are critical parts of the machinery governing NK cell-mediated killing of melanoma cells and indicate that NK cells could be harnessed to prevent melanoma metastasis. We aim to translate these findings into the clinic by proposing new NK cell-based immunotherapeutic strategies to treat melanoma patients and will also continue our research to understand the fundamental mechanisms of how, when, and where the immune system detects early signs of cancer.”
Illustration: Babraham Institute.
Babraham Institute News Release (04/09/09)
Abstract (Journal of Clinical Investigation; Vol. 119, Issue 5, 1251-1263 (05/01/09))