New strategy to tackle 'don’t eat me' signal on cancer cells4 March 2019• PRESSRELEASE
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.They published their results in Nature Medicine.
Researchers around the world are now looking for medicines to block CD47, the 'don't eat me' signal on cancer cells. One method for doing so is to intervene on the surface of the cell, by covering the CD47 molecules on cancer cells with a specific antibody. This method 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.
Screening the CD47 molecule
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 and working together with Scheeren, 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. 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. "Our genetic screen clearly shows that fundamental research is an important basis for translational and clinically relevant research", according to Scheeren.
Blocking the signal
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 route."
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 cancer.
Want to know more? Read the article ‘Glutaminyl cyclase is an enzymatic modifier 1 of the CD47- SIRPa axis 2 and target for immunotherapy’.
Funding: This research was partly funded by the European Research Council, the LUMC, the McDowell Cancer Foundation and the Dutch Cancer Society.