Catch the Invisibles
Cancer stem cells in leukemia protect themselves from the body's immune system by suppressing a molecule that is a target for killer cells. If this protective mechanism is overcome, it will be possible to develop a new concept for the treatment of leukemia.
NK cells (red) attack normal leukemia cells (green). Cancer stem cells (blue), in turn, suppress the expression of NKG2DL on their surface and thus avoid destruction by the immune system. Source: University and University Hospital of Basel.
Patients with acute myeloblastic leukemia (AML) often face relapse after seemingly successful treatment. This is the fault of cancer stem cells that survive during therapy, as they have protective mechanisms that make them resistant to chemotherapy. But how do they manage to avoid immune protection?
A group of scientists from the University Hospitals of Basel and Tubingen, the German Cancer Research Center (DKFZ), the Heidelberg Institute of Stem Cell Technology and Experimental Medicine (HI-STEM) and the German Cancer Consortium (DKTK) studied this problem and discovered an amazing mechanism.
The researchers analyzed the leukemia cells of 177 patients with AML and found that cancer stem cells lack expression of the NKG2D-L protein on the surface. This protein allows natural killer cells (NK cells) to recognize and kill damaged, infected, and cancer cells. By suppressing NKG2D-L, cancer stem cells avoid the attack of the immune system. Leukemic cells without stem cell properties have these target molecules on their surface and therefore can be seen by NK cells.
In mice that were implanted with human AML cells, NK cells controlled only AML cells without stem cell properties, while NKG2D-L-negative cancer stem cells avoided an immune response.
What is behind this reliable defense mechanism? The researchers noticed that cancer stem cells produce large amounts of the enzyme PARP1, which blocks the production of NKG2D-L. Preclinical experiments with mice transplanted with human AML cells showed that PARP1 really plays an important role in protecting against the immune system: treatment of animals with drugs that inhibit PARP1-induced NKG2D-L expression on the surface of leukemia stem cells led to recognition and destruction by injected human NK cells.
The results of the study offer opportunities to combat malignant leukemia stem cells by combining PARP inhibitors with active NK cells. The researchers plan to evaluate this approach in a clinical trial.
Article by A.M. Paczulla et al. The absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion is published in the journal Nature.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of DKFZ: Making cancer stem cells visible to the immune system - New results may enable innovative treatment concept against leukemia.