A Closer Look at the Immune Response to Cancer Cells

Leukocytes: Friend or Foe to Transformed Cells? Image of a neutrophil (red) gliding over a doublet of transformed mucus-producing cells
Last week it was reported that a daily (low) dose of aspirin can significantly reduce the risk of dying from a variety of cancers, and a study published in PloS Biology now opens a new window on the role of inflammation in cancer.

Although the host immune system is known to have conflicting roles in cancer initiation and progression, both acting as a surveillance and elimination system but also assisting expansion and metastatic spread of tumours, very little is known about the very early role of the immune system in cancer. Using zebrafish larvae, researchers at the University of Bristol, the University of Manchester and the FIRC Institute of Molecular Oncology in Milan have now been able to observe, for the first time, how oncogene-transformed cells in the skin co-opt the innate immune system to promote their growth from the very earliest stages of development. The team exploited the translucency of the larvae to obtain live images of the earliest interactions between the cancer cells and the immune environment. Using larvae with fluorescently tagged leukocytes, the team were able to observe recruitment of neutrophils and macrophages to oncogene-transformed melanocytes or mucus-secreting cells. As well as engulfment of the transformed cells, the team saw many examples of cytoplasmic tethers linking the two cell types.

They discovered that a key attractant for the leukocytes was hydrogen peroxide. Both the transformed cells themselves and otherwise healthy neighbouring cells were found to produce hydrogen peroxide, which is also a key molecule that recruits neutrophils to a wound. Blocking the synthesis of hydrogen peroxide prevented recruitment of immune cells and reduced the number of transformed cells, suggesting that immune cells may provide trophic support to the transformed cells just as they promote repair at a site of tissue injury. Unlike the case of wound healing, however, where the inflammatory response resolves, the inflammatory response to transformed cells seems to amplify and progress towards a chronic inflammatory state similar to that seen in chronic non-healing wounds.

Nickel Allergy Linked to Innate Immune Response

Image: Wikimedia Commons - Nicor
Nickel allergy is one of the most common causes of allergic contact dermatitis and a team led by researchers at the University of Giessen have now shown that the response is linked to activation of a single receptor, toll-like receptor 4 (TLR4).

The family of toll-like receptors normally recognizes structurally similar molecules derived from microbial pathogens and plays a key role in host defense. The team showed that nickel directly activated human, but not mouse, TLR4 and studies with mutant proteins showed that non-conserved histidine residues at positions 456 and 458 were necessary for activation of human TLR4. Wild type mice do not show an allergy to nickel but transgenic mice expressing human, rather than mouse, TLR4 could be efficiently sensitized to the metal. This is the first time that an inorganic substance has been shown to activate this innate immune pathway and, since histidines 456 and 458 are not essential for responses to microbial lipopolysaccharide, the authors suggest that site-specific inhibition of TLR4 could provide a potential strategy for treatment of nickel allergy, which would not compromise normal immune responses. Nickel allergy affects millions of people and is often associated with earrings and jewellery for other body piercings.

The study is published in the journal Nature Immunology.

Mouse T-cells Could Help in Fight Against Human Cancer

Mouse Biplane
Image: Wikimedia Commons - Wilfredor
T-cell receptors are integral membrane proteins that recognise foreign antigens and initiate a series of intracellular signalling cascades that allow the immune system to fight infection. To avoid autoimmune diseases, T-cells must be able to discriminate between ‘self’ and ‘foreign’ antigens but this discrimination may also prevent the immune system from recognising and destroying tumour cells.

Researchers led by a team from the Max-Delbrück-Center for Molecular Medicine have now developed transgenic mice that produce T-cell receptors that recognise human cancer cell antigens and could potentially be introduced into the T cells of cancer patients. Using embryonic stem cells loaded with human DNA, the team generated transgenic mice that express the entire human T-cell repertoire. Negative selection normally removes maturing T-cells that are capable of binding strongly to ‘self’ antigens but the mouse does not recognise human cancer cell antigens as ‘self’ and T-cells expressing receptors to these antigens are allowed to survive. T-cells with such high affinity receptors for cancer cell antigens are not produced in humans and the researchers hope that introducing the high affinity receptors into the T-cells of cancer sufferers will boost the immune system’s ability to recognise and destroy tumour cells. A first clinical trial to evaluate the efficacy and tolerability of the methodology in cancer patients is planned.

The study is published in the journal Nature Medicine.

Of Mice and Lice

mouseAn old adage says ‘we must all eat a peck of dirt before we die’, and there is increasing evidence linking the elimination of ‘dirt’ with a rising incidence of allergies and autoimmune disorders – the so-called ‘hygiene hypothesis’. More recently, a link between parasitic infections and the development of healthy immunoregulatory networks has been proposed.

There is evidence that worm infections in humans cause immunosuppression, and a team of scientists from the University of Nottingham has now shown a similar effect in populations of wild mice. Unlike laboratory animals, these mice were ‘naturally’ exposed to a variety of infections and so may provide a better insight into how the immune system functions in its natural context. The researchers used toll-like receptor (TLR) assays to provide an overall measure of immune function in response to a variety of parasites. After correcting for other variables, infection with both the nematode, H. polygyrus, and the louse, P. serrata, were found to suppress innate immunity, with a stronger effect produced by louse infections. It is perhaps surprising that the louse, just by attaching and feeding on the surface of the body can cause such a stronger immune response and the authors suggest that P. serrata could also secrete substances into the mouse that interfere directly with immune function or that the lice could act as a vector for an unidentified bacterial pathogen. The dampening of immune responsiveness associated with parasitic infections in wild mice supports the view that levels of innate immune activation in modern parasite-free human populations may be much greater than would have been typical during their recent evolutionary history, perhaps leading to an increased incidence of immune diseases.

The study is published in the journal BMC Biology.

A Bad Night’s Sleep Increases Risk of Catching Cold

sleepA good night’s sleep makes a big difference to how we feel, and a new US study suggests that it could also reduce our risk of catching a cold. People who sleep for fewer than seven hours a night were found to be almost three times more likely to get a cold than those who average eight or more hours a night. Having trouble falling asleep or waking up during the night increased the risk even more.

In the study, 54 out of 153 healthy men and women (average age 37) developed cold symptoms in the 5 days after nasal administration of drops containing a rhinovirus. After 28 days, blood samples were tested for antibodies to the virus and it was found that 135 people had become infected, although not all had developed a cold.

For two weeks before being exposed to the virus, the participants were asked each day about the duration and quality of their sleep. In the five days following exposure to the virus, people who had slept for fewer than seven hours each night in the previous two weeks were almost three times more likely to report symptoms than those who had slept for eight hours or more. Broken sleep was found to be even more important: those who were awake for more than 8% of sleep time were five and a half times more likely to show symptoms than those who were awake for 2% or less of the time. Interestingly, the development of cold symptoms did not correlate with how well rested the subjects felt. After taking into account a wide variety of other factors, how long – and especially how well – individuals slept were the strongest predictors of who would develop a cold. Previous research had suggested a link between sleep deprivation and impaired immune function, but this is the first study to show that sleep disturbances can affect susceptibility to cold viruses in normal healthy people. The study is published in the January 12th edition of Archives of Internal Medicine.