Myeloid immune cells kill cancer cells by eating them
but cancer cells prevent this from happening by giving out a 'do
not eat me' signal. Led by immunologist Ton Schumacher (Netherlands Cancer Institute
and Oncode) and Ferenc Scheeren (Leiden University Medical Center),
researchers from various research institutes have discovered a new
method to inhibit the 'do not eat me' signal, and have therefore
found a new target for immunotherapy.
On 4 March 2019, the researchers published an article on this topic in the scientific journal
The "don't eat me" signal
Different types of immune cells have different strategies to
fight cancer cells. For example, some immune cells-myeloid
cells-kill cancer cells by eating them. Cancer cells can prevent
this by expressing proteins on their surfaces which give out
inhibiting signals to the immune cells. One example is the 'do not
eat me' signal, officially called CD47, which ensures that the
cancer cell stays alive.
Researchers around the world are now looking for medicines to
block this "don't eat me" signal.
One method for doing so is to intervene on the surface of the
cell, by covering the CD47 molecules on cancer cells with a
This method of blocking the CD47 signal from cancer cells is
currently being clinically developed and is promising, but there
are side effects, such as a decrease in red blood cells. On top of
that, patients require a weekly IV to block the CD47 molecules on
cancer cells adequately.
Are there any other ways to counteract the "don't eat me" signal
CD47? To investigate this, PhD student Meike Logtenberg, lead
author of the article, set up a collaboration with experimental
geneticist Thijn Brummelkamp, who uses a unique method to map the
genetic regulation of any desired protein in a cell. "With this
screening method you can potentially find new targets," says Meike
Screening the CD47 molecule
Together with the immunologists, Brummelkamp screened CD47,
which also plays a role in healthy cells as an immune system check,
and found that the QPCTL enzyme is a crucial protein in forming the
"don't not eat me" signal. QPCTL changes the structure of the CD47
protein and without any QPCTL activity, the CD47 molecules are no
longer able to give off an inhibiting signal to myeloid cells.
Research leader Ton Schumacher: "In collaboration with the
groups of Jeanette Leusen (UMC Utrecht) and Timo van den Berg
(Sanquin Research), we then showed that as soon as we inhibited the
activity of this enzyme, we instantly blocked the "don't eat me"
signal on tumor cells. Identifying this new target is especially
relevant because the substances we can use to inhibit the QPCTL
enzyme are likely to have some advantages over the strategies
currently being clinically developed to inhibit the CD47 signal
Blocking the signal
With a QPCTL inhibitor, for example, it becomes easier to
control how long you want to block the signal, and so-called small
molecule inhibitors are easier to administer than antibodies.
Moreover, the substance does not inhibit the CD47 molecules on the
healthy red blood cells that a patient receives during a blood
transfusion to fight anaemia.
The researchers expect that QPCTL inhibitors will be available
for testing in clinical studies in the coming years. First clinical
trials are expected to take place in patients with blood
Logtenberg et al., 'Glutaminyl cyclase is an enzymatic modifier of the
CD47- SIRPa axis and target for cancer immunotherapy',
Nature Medicine 4 March 2019 (Advance Online
Corresponding author: Ton Schumacher
Funding: This research was partly funded by the European
Research Council, the LUMC, the McDowell Cancer Foundation and the
Dutch Cancer Society.