British Society for Haematology. Listening. Learning. Leading British Society for Haematology. Listening. Learning. Leading
25 July 2019

Scientists have discovered how some acute myeloid leukaemia (AML) stem cells escape the immune system – findings which pave the way for new, innovative treatments.

The project involved researchers from the Universities of Basel, Switzerland, and Tübingen, Germany, the German Cancer Research Centre (DKFZ), the Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) and the German Cancer Consortium (DKTK).

It is already known that leukaemia stem cells are responsible for the disease returning after treatment, in part because they have protective mechanisms that make them resistant to chemotherapy. In this new study, published in the journal Nature, the researchers set out to explain how leukaemia stem cells evade the immune system.

The research team analysed the leukaemia cells of 177 AML patients and found that the cancer stem cells reduce the presentation of NKG2D ligand (NKG2D-L) proteins on their surface.

It is these proteins that enable the natural killer cells (NK cells) to recognise – and kill, if necessary – damaged and infected cells, as well as cancer cells. The lack of these proteins on the surface of the leukaemia stem cells means the immune system does not destroy them.

Conversely, leukaemia cells without stem cell properties do present these molecules on their surface – and can then be kept in check by the NK cells.

In mouse models transplanted with AML cells, the team found that while normal AML cells without stem cell properties were controlled by NK cells, the NKG2D-L-negative leukaemia stem cells escaped.

Claudia Lengerke from the University Hospital of Basel and the University of Basel said: “Such a connection between stem cell properties and the ability to escape the immune system was unknown until now.”

The research scientists noticed that leukaemia stem cells produce a particularly high amount of the enzyme PARP1, and demonstrated that it blocked NKG2D-L production. Further experiments in mice carrying AML cells showed that PARP1 plays an important role in immune escape. For example, treatment with a PARP1 inhibitor induced the leukaemia stem cells to produce NKG2D-L, meaning the NK cells were able to attack them.

The results raise the possibility of combining PARP inhibitors with active NK cells to combat malignant leukaemia stem cells. The scientists involved are now planning to evaluate this approach in a clinical study.

Andreas Trumpp, German Cancer Research Centre and HI-STEM added: “Our results show how cancer stem cells cleverly trick the immune system. The elucidation of the underlying mechanism now makes it possible to counterattack.”


Source: Paczulla, A.M., Rothfelder, K., Raffel, S., Konantz, M., Steinbacher, J., Wang, H., Tandler, C., Mbarga, M., Schaefer, T., Falcone, M., Nievergall, E., Dörfel, D., Hanns, P., Passweg, J.R., Lutz, C., Schwaller, J., Zeiser, R., Blazar, B.R., Caligiuri, M.A., Dirnhofer, S., Lundberg, P., Kanz, L., Quintanilla-Martinez, L., Steinle, A., Trumpp, A., Salih, H.R., Lengerke, C. (2019) “Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion”, Nature, available from doi: 10.1038/s41586-019-1410-1

 

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