More than just a backup system: PI3K-Delta in tumour surveillance
If something is really important, it's best not to rely on it. This basic principle is followed equally by human engineers – for example, the NASA space shuttle has three main engines – and by nature. Thus it could be expected that each of the four subtly different forms of class I phosphoinositide 3-kinase (PI3K) works in much the same manner.
Class I PI3Ks add a phosphate group to phosphatidylinositol biphosphate, a phospholipid normally located on the inside of cell membranes, and thereby activate a number of important cellular processes. All four forms of the enzyme are expressed in T cells, suggesting that these cells have an 'insurance' system in place to protect them against the inadvertent loss of one or more form. Surprisingly, though, this is not the case and recent work by Eva Maria Putz, Michaela Prchal-Murphy and colleagues at the University of Veterinary Medicine, Vienna, has revealed that the body's defence against tumour cells absolutely requires the activity of one particular form. Their results were published recently in the prestigious online journal PLoS ONE and the authors comment on them in the current issue of the journal Oncoimmunology.
It has long been known that the four different forms of class I phosphoinositide 3-kinase (PI3K) in mammals are expressed in different tissues, with two forms – PI3K-Gamma and PI3K-Delta – essentially confined to blood cells. There had been indications that PI3K-Delta is important in controlling the secretion of cytokines from so-called helper T cells but its role in the functions of cytotoxic T cells had not previously been investigated. Cytotoxic T cells are cells of the immune system that respond to cancerous or virally infected cells, ultimately killing them and thus limiting the spread of the disease. The issue is not purely academic: a specific inhibitor of PI3K-Delta is being tested in clinical trials for use in the treatment of haematological malignancies, cancers that affect the blood, bone marrow and lymph nodes. It is important to investigate its effects on the human immune system to understand any potential long-term consequences of its use, thereby enabling detrimental side effects to be avoided or addressed.
In a longstanding collaboration with colleagues at the Medical University of Vienna – the scientists at the Vetmeduni acknowledge particularly the contribution of Eva Zebedin-Brandl – and with partners in Germany and Japan, Putz and Prchal-Murphy tested the ability of cytotoxic T cells from normal mice and from mice lacking PI3K-Delta to multiply when stimulated by the presence of a foreign protein. The cells lacking PI3K-Delta failed to respond, showing that although the enzyme form is not required for the normal proliferation of cytotoxic T cells, it is needed to enable the cells to proliferate in response to an attack. The scientists were able to show further that in the absence of PI3K-Delta cytotoxic T cells had far lower levels of the enzymes they normally rely on to kill diseased cells and were unable to release these enzymes when they should. They also produced lower levels of interferon-γ, a cytokine that is important in the defence against viruses.
By means of an elegant series of experiments, Putz and Prchal-Murphy were able to replicate their findings in mice, confirming that the lack of PI3K-Delta made the cytotoxic T cells far less effective at killing tumour cells. The result is that animals lacking PI3K-Delta develop larger tumours than mice in which this enzyme form is present. In other words, tumour surveillance absolutely requires the activity of PI3K-Delta.
The strict requirement for PI3K-Delta – as opposed to the other three forms of the enzyme – in the immune response to cancer was highly surprising and has important consequences for the treatment of haematological cancers, such as leukaemia, in humans. As both Putz and Prchal-Murphy say, "We know that inhibiting PI3K-Delta should slow the growth of the leukaemic cells but it will also stop normal cancer surveillance by cytotoxic T cells from working properly. This might be disadvantageous for cancer patients. On the other hand, it would be a huge help to people suffering from autoimmune diseases or to patients who have received transplants."
The paper "PI3Kd Is Essential for Tumor Clearance Mediated by Cytotoxic T Lymphocytes" was published by the open access journal PLoS ONE.
The comment "Targeting PI3Kδ - One man's meat is another man's poison" appears in the current issue of Oncoimmunology (Vol. 2(1) 2013, pp. 1‑2).
Journal reference: PLoS ONE
Provided by Medical University of Vienna
- Targeted agent shows promise for chronic lymphoid leukemia Sep 13, 2010 | not rated yet | 0
- Treatment targeting PI3K may delay resistance to anti-HER2 therapy in breast cancer patients Jan 23, 2013 | not rated yet | 0
- Therapy exploits 'addiction' of leukemia cells Apr 16, 2012 | not rated yet | 0
- Study identifies potential treatment for lethal childhood leukemia Apr 16, 2012 | not rated yet | 0
- Hedgehog pathway key in tamoxifen-resistant breast CA Nov 06, 2012 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
Alcohol and acetaminophen
May 13, 2013 Edit: sorry for the typo in the title , can't edit I looked around on google quite a bit and it's very hard to find precise information on the...
Marie Curie's leukemia
May 13, 2013 Does anyone know what might be the cause of Marie Curie's cancer
- More from Physics Forums - Medical Sciences
More news stories
The use of a smartphone application significantly improves patients' preparation for a colonoscopy, according to new research presented today at Digestive Disease Week (DDW). The preparation process, which begins days in ...
Cancer 6 hours ago | not rated yet | 0
Research presented at Digestive Disease Week (DDW) explores new methods for managing digestive health through diet and lifestyle.
Cancer 6 hours ago | not rated yet | 0
A ground-breaking advance in colonoscopy technology signals the future of colorectal care, according to research presented today at Digestive Disease Week(DDW). Additional research focuses on optimizing the minimal withdrawal ...
Cancer 21 hours ago | 5 / 5 (2) | 0
(HealthDay)—Concurrent use of two immune checkpoint antibodies—ipilimumab and nivolumab—may be effective for the treatment of advanced melanoma, according to a proof-of-principal study presented in ...
Cancer May 17, 2013 | not rated yet | 0
(HealthDay)—The risks of metastasis and death associated with cutaneous squamous cell carcinoma (CSCC) are low, but significant, and risk factors for poor outcome include tumor diameter, invasion beyond ...
Cancer May 17, 2013 | not rated yet | 0 |
Regular consumption of coffee is associated with a reduced risk of primary sclerosing cholangitis (PSC), an autoimmune liver disease, Mayo Clinic research shows. The findings were being presented at the Digestive Disease ...
6 hours ago | not rated yet | 0 |
Patients with treatment-resistant major depression saw dramatic improvement in their illness after treatment with ketamine, an anesthetic, according to the largest ketamine clinical trial to-date led by researchers from the ...
6 hours ago | 4.5 / 5 (2) | 0 |
There are significant cost and risk factors associated with two procedures commonly used to diagnose or treat gastrointestinal problems, according to research presented at Digestive Disease Week (DDW).
6 hours ago | not rated yet | 0
An increasing number of U.S. children are experiencing gastrointestinal issues that require interventions to resolve, according to research presented at Digestive Disease Week (DDW).
21 hours ago | not rated yet | 0 |
The latest makeover to a massive psychiatric tome honored by some, reviled by others and even called the "Bible" of mental disorders is being released Saturday with a host of new changes.
18 hours ago | not rated yet | 0
A new case of the deadly coronavirus has been detected in Saudi Arabia where 15 people have already died after contracting it, the health ministry announced on Saturday on its Internet website.
19 hours ago | not rated yet | 0