Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion

Paczulla, Anna M. and Rothfelder, Kathrin and Raffel, Simon and Konantz, Martina and Steinbacher, Julia and Wang, Hui and Tandler, Claudia and Mbarga, Marcelle and Schaefer, Thorsten and Falcone, Mattia and Nievergall, Eva and Dörfel, Daniela and Hanns, Pauline and Passweg, Jakob R. and Lutz, Christoph and Schwaller, Juerg and Zeiser, Robert and Blazar, Bruce R. and Caligiuri, Michael A. and Dirnhofer, Stephan and Lundberg, Pontus and Kanz, Lothar and Quintanilla-Martinez, Leticia and Steinle, Alexander and Trumpp, Andreas and Salih, Helmut R. and Lengerke, Claudia. (2019) Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion. Nature, 572 (7768). pp. 254-259.

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Official URL: https://edoc.unibas.ch/80788/

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Patients with acute myeloid leukaemia (AML) often achieve remission after therapy, but subsequently die of relapse; 1; that is driven by chemotherapy-resistant leukaemic stem cells (LSCs); 2,3; . LSCs are defined by their capacity to initiate leukaemia in immunocompromised mice; 4; . However, this precludes analyses of their interaction with lymphocytes as components of anti-tumour immunity; 5; , which LSCs must escape to induce cancer. Here we demonstrate that stemness and immune evasion are closely intertwined in AML. Using xenografts of human AML as well as syngeneic mouse models of leukaemia, we show that ligands of the danger detector NKG2D-a critical mediator of anti-tumour immunity by cytotoxic lymphocytes, such as NK cells; 6-9; -are generally expressed on bulk AML cells but not on LSCs. AML cells with LSC properties can be isolated by their lack of expression of NKG2D ligands (NKG2DLs) in both CD34-expressing and non-CD34-expressing cases of AML. AML cells that express NKG2DLs are cleared by NK cells, whereas NKG2DL-negative leukaemic cells isolated from the same individual escape cell killing by NK cells. These NKG2DL-negative AML cells show an immature morphology, display molecular and functional stemness characteristics, and can initiate serially re-transplantable leukaemia and survive chemotherapy in patient-derived xenotransplant models. Mechanistically, poly-ADP-ribose polymerase 1 (PARP1) represses expression of NKG2DLs. Genetic or pharmacologic inhibition of PARP1 induces NKG2DLs on the LSC surface but not on healthy or pre-leukaemic cells. Treatment with PARP1 inhibitors, followed by transfer of polyclonal NK cells, suppresses leukaemogenesis in patient-derived xenotransplant models. In summary, our data link the LSC concept to immune escape and provide a strong rationale for targeting therapy-resistant LSCs by PARP1 inhibition, which renders them amenable to control by NK cells in vivo.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin
UniBasel Contributors:Konantz, Martina
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Research
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:09 Jun 2021 13:52
Deposited On:09 Jun 2021 13:52

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