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By carefully adjusting the function of crucial immune cells, scientists may have developed a completely new type of cancer immunotherapy - harnessing the body's immune system to attack tumors. To accomplish this, they had to thread a needle in immune function, shrinking tumors without triggering unwanted autoimmune responses.
The new research, performed in animals, is not ready for clinical use in humans. However, the approach, making use of a key protein to control immune function, lends itself to further study using candidate drugs that employ the same mechanisms.
"This preclinical study demonstrates proof of principle that using a drug to regulate the function of a special, immunosuppressive subset of so-called T-regulatory (Treg) cells safely controls tumor growth," said study leader Wayne W. Hancock, M.D., Ph.D., of the Division of Transplant Immunology at The Children's Hospital of Philadelphia (CHOP). "It really moves the field along towards a potentially major, new cancer immunotherapy."
Hancock and colleagues published the study in Nature Medicine.
"There's a basic paradox in immunology: why doesn't the immune system prevent cancer in the first place?" said Hancock. The answer is complicated, he adds, but much of it involves a delicate balancing act among elements of the immune system: while immunity protects us against disease, an overly aggressive immune response may trigger dangerous, even life-threatening, autoimmune reactions in which the body attacks itself.
In the current study, Hancock focused on a subtype of immune cells called Foxp3+ Tregs, for short. Tregs were already known to limit autoimmunity, but often at the cost of curtailing immune responses against tumors. "We needed to find a way to reduce Treg function in a way that permits antitumor activity without allowing autoimmune reactions," he said.
Hancock's group showed that inhibiting the enzyme p300 can affect the functions of another protein, Foxp3, which plays a key role in controlling the biology of Tregs. By deleting the gene that expresses p300, the researchers safely reduced Treg function and limited tumor growth in mice. Notably, they also achieved the same effects on p300 and Tregs in mice by using a drug that inhibits p300 in normal mice.
Hancock will pursue further investigations into targeting p300 in immunotherapy. The preclinical findings offer encouraging potential for being translated into the clinic, said Hancock, who added that pharmaceutical companies have expressed interest in researching this approach as a possible cancer therapy.
The antitumor study, down-regulating Treg function, is the flip side of another part of Hancock's Treg research. In a 2007 animal study, also in Nature Medicine, he increased Treg function with the goal of suppressing the immune response to allow the body to better tolerate organ transplants. In the current study, decreasing Treg activity permitted the immune system to attack an unwelcome visitor - a tumor. In both cases, he relied on epigenetic processes - using groups of chemicals called acetyl groups to modify key proteins - but in opposite directions. "This is the yin and yang of immune function," he added.
Article adapted by Medical News Today from original press release. Click 'references' tab above for source.The National Institutes of Health (grants AI073489, AI095353, and CA158941, all to Hancock) supported this research. In addition to his CHOP position, Hancock is on the faculty of the Perelman School of Medicine at the University of Pennsylvania.
Yujie Liu et al., "Inhibition of p300 impairs Foxp3+ T regulatory cell function and promotes antitumor immunity," Nature Medicine, published online Aug. 18, 2013. doi:10.1038/nm.3286
Children's Hospital of Philadelphia
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Male fruit flies have one X chromosome per cell, females have two. So genes on the male X must work twice as hard to produce the same amount of protein as its female counterparts. An LMU team has found a new switch involved in making this possible.
In the fruit fly Drosophila - as in humans - the sexes have different sets of chromosomes. While females have two X chromosomes in their somatic cells, males have one X and one copy of the much smaller Y. The latter determines maleness but carries very few genes, while the X chromosome has thousands of genes. Many of these encode essential proteins that must be made in equal amounts in both sexes, and males that fail to meet this requirement are inviable.
The males make up for the difference in X chromosome copy number by ensuring that each gene on their X chromosome is expressed at twice the rate of its equivalent on a female X, a phenomenon known as dosage compensation. The so-called Dosage Compensation Complex (DCC) is responsible for distinguishing the X chromosome from the others in males and doubling the level of activity of most of the genes it contains. The DCC is a complicated molecular machine which, in addition to so-called MSL proteins, contains two long RNA molecules (referred to as roX RNAs). "Correct incorporation of roX RNAs is known to be essential for DCC function, but how this is accomplished has been unclear," says LMU biologist Professor Peter Becker, who studies how the operation of the DCC is regulated.
Switching to the binding mode
Members of his team have now discovered that a change in the structural conformation of the roX RNAs is a prerequisite for the functional activation of DCC. These RNAs all contain a characteristic hairpin structure, which is conserved in various fly species. "We have long supposed that such a widely conserved structure must be of functional significance, but we were unable to demonstrate a specific binding interaction between the hairpin and the MSL protein components of the DCC", Becker explains.
The reason for this is revealed in the new study. It turns out that the hairpin structure actually prevents protein binding. The hairpin must first be unwound by a specific enzyme before the MSL proteins can bind to the RNAs and a functional DCC is formed. The closed hairpin conformation is equivalent to a switch fixed in the OFF position. Unwinding of the hairpin flips the switch to ON, thus permitting assembly of the active DCC. "We believe that this switch is only activated under conditions that are found at certain sites on the X chromosome. This would ensure that dosage compensation is restricted to genes on the X", says Becker.
The researchers now assume that long RNAs play a much more active role in other regulatory complexes than has been suspected hitherto. Up to now, these RNAs have been seen as passive scaffolds for the binding of proteins. "We think though that they modulate the activity of the proteins they associate with. And we have now shown this for the DCC", Becker says. He will continue to work in this field. "Now it's getting really exciting," he says.
Article adapted by Medical News Today from original press release. Click 'references' tab above for source.ATP-Dependent roX RNA Remodeling by the Helicase maleless Enables Specific Association of MSL Proteins, Sylvain Maenner, Marisa Müller, Jonathan Fröhlich, Diana Langer, Peter B. Becker, doi: 10.1016/j.molcel.2013.06.011, Molecular Cell 2013
The study was supported by grants from the DFG to the Collaborative Research Center Transregio 5, and by an EU-funded ERC Advanced Grant for the project “Assembly and maintenance of a co-regulated chromosomal compartment” (ACCOMPLI).
Ludwig-Maximilians-Universität München
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