PARP1 Inhibition Overcomes Immune Escape of Leukemic Stem Cells from NK cells

Chemotherapy-resistant leukemic stem cells (LSC) contribute to relapse after initial remission of acute myeloid leukemia (AML). Paczulla, Rothfelder, Raffel, and colleagues found that bulk AML cells, but not LSCs, express ligands of the immunoreceptor NKG2D. Screening 177 patients with AML for expression of NKG2D-recognized ligands (NKG2DL) revealed heterogeneity in AML cells derived from individual patients. The NKG2DL⁻ leukemic population showed increased in vitro clonogenicity compared to NKG2DL⁺ cells and contained virtually all leukemia-initiating activity as assayed by xenotransplantation. Leukemic infiltration of bone marrow and other organs was observed in mice transplanted with NKG2DL⁻ cells but not with NKG2DL⁺ cells, and the former group also showed reduced overall survival. While NKG2DL⁻ cells in engrafted mice generated NKG2DL⁻ and NKG2DL⁺ progeny, the NKG2DL⁺ cells were not leukemogenic in this assay. Mice engrafted with AML cells and treated with the chemotherapy agent cytarabine showed loss of NKG2DL⁺ leukemia cells, while NKG2DL⁻ cells persisted, demonstrating their increased chemoresistance. In agreement with this finding, AML patients displaying higher proportions of NKG2DL⁺ cells had better responses to chemotherapy and longer overall survival. Gene-expression arrays and RNA sequencing revealed PARP1 to be more highly expressed in NKG2DL⁻ cells, and high PARP1 expression correlated with poor clinical outcome in patients with AML. Importantly, genetic or pharmacologic inhibition of PARP1 induced expression of NKG2DLs on CD34⁺ leukemic but not healthy hematopoietic stem/progenitor cells. This finding thus links inhibition of PARP1 to immune-sensitization of AML cells towards NK cell immune surveillance. Treatment of mice transplanted with AML cells with a PARP1 inhibitor, followed by transfer of human NK cells, suppressed leukemogenesis in vivo. Together, these results link the concepts of cancer stemness and immune evasion, both considered hallmarks of cancer. They reveal that lack of NKG2DL expression is a marker for LSCs and imply that exploitation of PARP inhibition to restore NKG2DL expression in combination with NK cell transfer may be a useful strategy to reduce the chance of relapse in AML.

Paczulla AM, Rothfelder K, Raffel S, Konantz M, Steinbacher J, Wang H, et al. Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion. Nature 2019 Jul 17 [Epub ahead of print].

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