Welcome to our fifth installment of our new regular monthly slot where we report on research from the world of immunology, highlighting work from BSI members that has hit the headlines over the past four weeks.
Novel targets identified for cancer and inflammatory diseases
Exciting new research from the Francis Crick Institute and King’s College London suggests novel targets for cancer and inflammatory diseases. Residing in the epithelial cells that line our skin and gut are specialised T cell compartments that run tight immune surveillance on local tissues. Stimulation of these T cells is mediated by key proteins identified in this study: butyrophilin-like molecules.
Identification of all members of this protein family should help form the foundation for determining how these molecules might be altered during gut development, cancerous transformation, infection, and inflammation to activate epithelial-bound T cells. Understanding the mechanisms could sensitise the system to eliminate tumours, or suppress the system to treat inflammatory diseases such as colitis or dermatitis.
Published in Cell, BSI member Professor Adrian Hayday explains the value of his study: “We need to know how such tissue-resident immune cells sense the status of the body surface in which they sit. How do the cells know when things are not normal and that they need to respond? And how do they know what responses to make? Answering these questions could provide major clues to how the immune system monitors cancer and contributes to skin and gut inflammation.”
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Read the full article: Di Marco Barras et al. 2016 Cell doi: 10.1016/j.cell.2016.08.030
Dying tumour cells release potassium ions to impede T cell effector functions
The tumour microenvironment contains rapidly dividing rogue cells that compete for limited resources. As a consequence, dense regions of dying cells accumulate, releasing high concentrations of potassium into the extracellular milieu as they rupture. As researchers from the Babraham Institute and the US-based National Cancer Institute discovered, this localised increase in potassium concentration subdues the anti-tumour activity of T cells.
Other ions, including calcium, magnesium and sodium, have previously been associated with diminished human T cell function but, as lead researcher Dr Rahul Roychoudhuri explains, “While ions such as calcium are known to play critical roles in the activation of T cells when they encounter foreign invaders and cancer cells, very little was known about how extracellular potassium might affect this. Surprisingly, we found that high levels of potassium, which was released by dying cells in tumours, had very little effect on calcium but blocked activation of a cellular signalling pathway called the PI3K pathway when T cells encountered tumour antigens”.
To reverse the attenuating effects of potassium on T cell effector function, the team genetically engineered tumour-specific T cells to express additional molecular pumps that specifically remove surplus potassium from the cell. As such, these T cells exhibited improved anti-tumour functionality. This research, published in Nature, also exposes new mechanisms for cancer immunotherapies.
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Read the full article: Eil et al. 2016 Nature doi: 10.1038/nature19364
Interferon lambda proves to be an effective anti-viral
Positive results for a possible new flu treatment were recently published inEMBO Molecular Medicine. Researchers at the Francis Crick Institute treated influenza-infected mice with either interferon alpha, interferon lambda, or provided no treatment at all. 50% of those without treatment died. 20% died following treatment with interferon alpha, while an impressive 80% survived with interferon lambda. Similar results were observed when the experiment was replicated in human cells.
Interferons are produced naturally by the body in response to viral infection. However, only interferon lambda appears to exert a protective effect. While interferon alpha effectively reduced the number of viral particles in this investigation, it also activated a strong inflammatory response, contributing towards tissue damage in the lungs. In contrast, interferon lambda did not provoke pro-inflammatory effects, thereby inducing a more favourable outcome.
BSI member Dr Andreas Wack is enthusiastic about its potential as a treatment option. “We know interferon lambda has a decent safety profile as it has already been tested for safety in humans. It passed phase 1 and 2 clinical trials as a hepatitis C therapy before better treatment options were found for that disease. If it were to be considered as an influenza treatment, this means the starting point to test it would be relatively advanced.” The team are also hopeful that the therapeutic effects of interferon lambda are not limited to influenza, but could also be used to treat other viruses that cause respiratory disease.
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Read the full article: Davidson et al. 2016 EMBO Molecular Medicine doi:10.15252/emmm.201606413