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

Abstract

Data availability statement. All data generated are included in the published article and in the Supplementary Information. Gene expression data that support the findings of this study have been deposited in the Gene Expression Omnibus under accession numbers GSE127200 and 127959. All data are also available from the authors on reasonable request.

To PARP or not to PARP?—Toward sensitizing acute myeloid leukemia stem cells to immunotherapy

“…Low or absent expression of NK cell‐activating receptor ligands (NKG2DLs) of the MIC and ULBP families, as well as secretion of soluble NKG2DLs in AML, is well established as a strategy for immune escape employed by leukemia cells (Nowbakht et al , ; Hilpert et al , ). However, Paczulla et al () here provide the first demonstration that the absence of NKG2DLs is a defining characteristic of LSCs and that PARP1 inhibition can restore NKG2DL expression thus sensitivity to NK cell immune surveillance. Interestingly, the investigators also found that previously reported stimuli to promote NKG2DL expression in leukemia cells, such as all‐trans retinoic acid (ATRA), valproic acid, and azacitidine, were not able to enhance NKG2DL expression by LSCs (Paczulla et al , ).…”

“…However, Paczulla et al () here provide the first demonstration that the absence of NKG2DLs is a defining characteristic of LSCs and that PARP1 inhibition can restore NKG2DL expression thus sensitivity to NK cell immune surveillance. Interestingly, the investigators also found that previously reported stimuli to promote NKG2DL expression in leukemia cells, such as all‐trans retinoic acid (ATRA), valproic acid, and azacitidine, were not able to enhance NKG2DL expression by LSCs (Paczulla et al , ). Both IFNα and IL‐15 have also been demonstrated to enhance NK cell cytotoxic function as well as to promote expression of cell surface NKG2DLs on leukemia cells (Szczepanski et al , , Zhang et al , ); however, these were not explored in the current study.…”

“…Paczulla et al () reveal that leukemia stem cells (LSCs) are defined by their lack of expression of cell surface ligands for the NKG2D activating receptor on natural killer (NK) cells. The absence of NKG2DLs confers resistance to NK cell‐mediated immune surveillance.…”

“…In summary, Paczulla et al () make the seminal observation that PARP1 inhibition combined with adoptive transfer of polyclonal NK cells can prevent leukemogenesis, which will likely have significant implications for the treatment of patients with AML. Current NK cell immunotherapy approaches for the treatment of AML primarily focus on allogeneic NK cell transplantation, which exploits the graft versus leukemia effect of NK cell alloreactivity.…”

“…Current NK cell immunotherapy approaches for the treatment of AML primarily focus on allogeneic NK cell transplantation, which exploits the graft versus leukemia effect of NK cell alloreactivity. The novel findings by Paczulla et al () provide a rationale to use PARP1 inhibition in combination with NK cell‐based immunotherapy to enhance NK cell recognition of LSCs and underscore the importance of NKG2DL expression in AML. However, PARP1 inhibition in the setting of bone marrow failure syndromes and leukemia may result in protracted myelosuppression necessitating intensive monitoring.…”