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

Anna M. Paczulla, Kathrin Rothfelder, Simon Raffel, Martina Konantz, Julia Steinbacher, Hui Wang, Claudia Tandler, Marcelle Mbarga, Thorsten Schaefer, Mattia Falcone, Eva Nievergall, Daniela Dörfel, Pauline Hanns, Jakob R. Passweg, Christoph Lutz, Juerg Schwaller, Robert Zeiser, Bruce R. Blazar, Michael A. Caligiuri, Stephan Dirnhofer, Pontus Lundberg, Lothar Kanz, Leticia Quintanilla-Martinez, Alexander Steinle, Andreas Trumpp, Helmut R. Salih () and Claudia Lengerke
Additional contact information
Anna M. Paczulla: University of Basel and University Hospital Basel
Kathrin Rothfelder: German Cancer Consortium (DKTK)
Simon Raffel: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Martina Konantz: University of Basel and University Hospital Basel
Julia Steinbacher: German Cancer Consortium (DKTK)
Hui Wang: University of Basel and University Hospital Basel
Claudia Tandler: German Cancer Consortium (DKTK)
Marcelle Mbarga: University of Basel and University Hospital Basel
Thorsten Schaefer: University of Basel and University Hospital Basel
Mattia Falcone: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Eva Nievergall: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Daniela Dörfel: Eberhard-Karls University
Pauline Hanns: University of Basel and University Hospital Basel
Jakob R. Passweg: University Hospital Basel
Christoph Lutz: Heidelberg University Hospital
Juerg Schwaller: University of Basel and University Hospital Basel
Robert Zeiser: University Medical Center Freiburg
Bruce R. Blazar: University of Minnesota
Michael A. Caligiuri: City of Hope National Medical Center
Stephan Dirnhofer: University Hospital Basel
Pontus Lundberg: University Hospital Basel
Lothar Kanz: Eberhard-Karls University
Leticia Quintanilla-Martinez: University of Tuebingen
Alexander Steinle: Goethe University
Andreas Trumpp: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Helmut R. Salih: German Cancer Consortium (DKTK)
Claudia Lengerke: University of Basel and University Hospital Basel

Nature, 2019, vol. 572, issue 7768, 254-259

Abstract: Abstract Patients with acute myeloid leukaemia (AML) often achieve remission after therapy, but subsequently die of relapse1 that is driven by chemotherapy-resistant leukaemic stem cells (LSCs)2,3. LSCs are defined by their capacity to initiate leukaemia in immunocompromised mice4. However, this precludes analyses of their interaction with lymphocytes as components of anti-tumour immunity5, 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 cells6–9—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.

Date: 2019
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DOI: 10.1038/s41586-019-1410-1

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