Targeting SUMOylation Triggers IFN-β-dependent Activation of Patient and Allogenic NK Cells in Preclinical Models of Acute Myeloid Leukemia.

NK cells can play a significant role in the antitumoral immune response. In patients with acute myeloid leukemia (AML), NK cells are, however, often found in low numbers and exhibit poor activity, contributing to leukemic progression. Allogenic NK cells are emerging as promising cellular therapies for hematologic cancer treatment. New strategies are however required to both reactivate NK cells in patients with AML and enhance the antitumor activity of transplanted NK cells. In this study, we demonstrate that targeting SUMOylation, a protein posttranslational modification, activates NK cells from both healthy donors and patients with AML. Subasumstat (TAK-981), a first-in-class inhibitor of SUMOylation used in phase I/II clinical trials, enhances NK cell degranulation, secretion of inflammatory cytokines (IFN-γ, TNF-α, and FasL), and cytotoxicity against AML cells. In vivo, TAK-981 improves the anti-leukemic efficacy of ex vivo expanded cord blood NK cells in leukemia-bearing mice. One early effect of TAK-981 is to specifically increase the accessibility and activation of cis-regulatory regions of IFN-I pathway genes and induce their transcription. TAK-981-induced secretion of IFN-β, mostly by NK cells and myeloid cells, is required for NK cell activation. Surprisingly, IFNB1 induction does not require its best-characterized activators MDA5, cGas, and IFN response factor-1, -3, and -7. Altogether, this suggests that targeting SUMOylation activates a noncanonical IFN-I pathway, which enhances the anti-leukemic potential of NK cells.