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Targeting SUMOylation triggers interferon-beta-dependent activation of patient and allogenic Natural Killer cells in preclinical models of Acute Myeloid Leukemia [ATAC-seq I]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263923 | GEO | 2025/06/18

REPOSITORIES: GEO

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Project description:Mantle cell lymphoma (MCL) is a rare, highly heterogeneous type of B-cell non-Hodgkin’s lymphoma (NHL) driven by multiple genetic mutations disrupting cell cycle regulation and DNA damage response. Despite advances in therapy, novel treatment approaches are needed especially for highly proliferative MCL which has a particularly progressive clinical course even in the era of Bruton’s tyrosine kinase therapy. The sumoylation pathway is known to be upregulated in many cancers including lymphoid malignancies. However, little is currently known about the role of the sumoylation pathway and its oncogenic potential in MCL. We found extensive upregulation of the sumoylation pathway in MCL, particularly at the level of the E1 enzymes SAE1 and SAE2, with elevated expression levels of sumoylation enzyme components showing a worse prognosis and a strong positive correlation with cell cycle associated genes. Targeting the sumoylation pathway with TAK-981, a first in class sumoylation inhibitor currently being investigated in a clinical study of B-cell NHL in combination with rituximab (NCT04074330), resulted in potent loss of sumoylation in MCL cells with significant activity in in-vitro and in vivo models of MCL, including ibrutinib resistance cases. We found mitotic dysregulation to be an important, although not all encompassing mechanism of cell death upon loss of sumoylation of TAK-981 in MCL cells. We uncovered a diverse sumoylation program upon mitosis entry that was significantly reduced with TAK-981. Centromeric localization of the well known sumoylation substrate topoisomeraseIIA (TopIIA) was significantly abrogated upon mitosis entry, likely contributing at least in part to the mitotic dysregulation seen in MCL cells. This mechanism is highly relevant as TopIIA is significantly upregulated in MCL with SAE1/2 overexpression. Our study, in addition to the recently described immunomodulatory activity of TAK-981, not only validates SAE1/2 as a therapeutic target in MCL but also opens the door to further mechanistic work to uncover how to best use desumoylation therapy to treat MCL and other lymphoid malignancies.

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Targeting SUMOylation triggers interferon-beta-dependent activation of patient and allogenic Natural Killer cells in preclinical models of Acute Myeloid Leukemia [ATAC-seq I]

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