Targeting SUMOylation triggers interferon-ß-dependent activation of patient and allogenic Natural Killer cells in preclinical models of Acute Myeloid Leukemia.

Natural Killer (NK) cells can play a significant role in the anti-tumoral 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 hematological cancer treatment. New strategies are however required to both reactivate NK cells in AML patients and enhance the anti-tumor activity of transplanted NK cells. Here, we demonstrate that targeting SUMOylation, a protein post-translational modification, activates NK cells from both healthy donors and AML patients. Subasumstat (TAK-981), a first-in-class inhibitor of SUMOylation used in phase I/II clinical trials, enhances NK cells degranulation, secretion of inflammatory cytokines (IFN-γ, TNF-α, 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 type I interferon (IFN-I) pathway genes and induce their transcription. TAK-981-induced secretion of interferon-ß, mostly by NK cells and myeloid cells, is required for NK cells activation. Surprisingly, IFNB1 induction does not require its best-characterized activators MDA5, cGas, IRF-1, -3 and -7. Altogether, this suggests that targeting SUMOylation activates a non-canonical IFN-I pathway, which enhances the anti-leukemic potential of NK cells.