Targeting SUMOylation triggers interferon-beta-dependent activation of patient and allogenic Natural Killer cells in preclinical models of Acute Myeloid Leukemia [CUT&RUN]

Natural Killer (NK) cells are critical actors of the anti-tumoral immune response. However, NK cells are often dysfunctional in cancer patients, particularly in hematological malignancies like Acute Myeloid Leukemias (AML), where patients typically exhibit low NK cells numbers and activity. In addition, there is increasing interest in using allogenic NK cells transplantation as cancer immunotherapy. New strategies are however required to both reactivate NK cells in cancer 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 interferon pathway genes and induce their transcription. TAK-981 induces the secretion of interferon-beta, mostly by NK cells and monocytes, which is required for NK cells activation. Surprisingly, IFNB1 induction is independent of MDA5, cGas, IRF-1, -3 and -7. Altogether, this suggests that targeting SUMOylation activates a non-canonical interferon pathway able to boost NK cells anti-leukemic potential.