Leukemic stem cells hiding in plain sight

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Science Immunology  02 Aug 2019:
Vol. 4, Issue 38, eaay7253
DOI: 10.1126/sciimmunol.aay7253


Activation of NK-mediated immune surveillance clears leukemic stem cell populations.

Current immunotherapy approaches have shown only limited effects in cancers such as acute myeloid leukemia (AML), where persistence of leukemic stem cells (LSCs) after chemotherapy likely contributes to the high rate of disease relapse. LSCs are defined, in part, by their potential to initiate and propagate leukemia in immunocompromised mice, which complicates the functional evaluation of immune evasion mechanisms in these cell populations. There is a well-documented role of NK cells in promoting graft-versus-leukemia effects in patient status/post allogeneic stem cell transplantation, and NK cell-based immunotherapy is active area of investigation for the treatment of AML. The mechanisms by which AML blasts, and LSCs in particular, evade NK cells are poorly understood.

Paczulla and colleagues studied the functional impact of NKG2D ligand expression in AML. Of note, expression of NKG2D ligands in AML has been previously observed to associate with better overall survival, presumably as a consequence of triggering NK-mediated cell killing via the NKG2D receptor. Interestingly, the authors found that although NKG2D ligands were heterogeneously expressed in bulk AML blast populations, they were consistently absent in LSC populations, which suggests a mechanism of escape from immune surveillance. In further studies using co-culture of primary AML samples with polyclonal NK cells, the authors demonstrated that NK-mediated immune surveillance leads to the preferential depletion of the non-LSC populations that express NKG2D ligands, and the corresponding enrichment of the LSC populations that lack NKG2D ligands. Notably, this effect was abrogated in the presence of NKG2D blocking antibodies. Finally, the authors also showed that genetic ablation or pharmacologic inhibition of PARP1 in LSC populations leads to the de-repression of NKG2D ligands and activation of NK-mediated tumor clearance in vivo, which was not observed upon inhibition of PARP1 in normal stem cell or progenitor populations. These results lay the groundwork for further studies with clinically available PARP1 inhibitors to test whether this strategy can promote the immune-mediated clearance of persistent LSC populations in AML.

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