New strategy to tackle 'don't eat me' signal on cancer cells

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. In a collaborative effort, the Netherlands Cancer Institute, Oncode, Leiden University Medical Center and University Medical Center Utrecht have discovered a new method to inhibit the 'don't eat me' signal, and have therefore found a new strategy for immunotherapy.

On 4 March 2019, the researchers published an article on this topic in the scientific journal Nature Medicine.

 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 CD47 molecule that provides a 'don't eat me' signal, which enables the cancer cell to survive.

Researchers around the world are 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 specific antibody. (see for example Advani et al, N Engl J Med. 2018 379:1711, and Valerius, Rösner and Leusen, N Egl J Med, 2019, 380:496)

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.

 Screening the CD47 molecule

To search for new strategies to block CD47, Meike Logtenberg, first author on the paper worked with Thijn Brummelkamp to genetically screen CD47 and found one hit: QPCTL. This enzyme is crucial in forming the "don't eat me" signal, because it alters the CD47 protein.

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’. In preclinical models, performed by Marco Jansen in the group of Jeanette Leusen, it became evident that cancer cells could only be killed with an antibody, when the enzyme was removed.

 Advantages for therapy

Inhibitors of QPCTL can be given to patients as pills, whereas antibodies need to be given as intravenous infections. With these inhibitors, it is also easier to control the duration of the effect. Moreover, they do not inhibit the CD47 molecules on the healthy red blood cells that a patient receives during a blood transfusion to fight anemia.

 Clinical studies

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.

Meike E. W. Logtenberg et al. Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPα axis and a target for cancer immunotherapy, Nature Medicine (2019). DOI: 10.1038/s41591-019-0356-z

Funding: This research was financed by the European Research Council, the LUMC, the McDowell Cancer Foundation and the Dutch Cancer Society (KWF)(UMCU).