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 DirnhoferPontus Lundberg, Lothar Kanz, Leticia Quintanilla-Martinez, Alexander Steinle, Andreas Trumpp, Helmut R. Salih, Claudia Lengerke

Research output: Contribution to journalLetter

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)254-259
Number of pages6
JournalNature
Volume572
Issue number7768
DOIs
StatePublished - Aug 8 2019

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PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

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., ... Lengerke, C. (2019). Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion. Nature, 572(7768), 254-259. https://doi.org/10.1038/s41586-019-1410-1