T Cell–intrinsic Immunomodulatory Effects of TAK-981 (Subasumstat), a SUMO-activating Enzyme Inhibitor, in Chronic Lymphocytic Leukemia

Abstract

Novel targeted agents used in therapy of lymphoid malignancies are recognized to have complex immune-mediated effects. Sumoylation, a posttranslational modification of target proteins by small ubiquitin-like modifiers (SUMO), regulates a variety of cellular processes indispensable in immune cell activation. Despite this, the role of sumoylation in T cell biology in context of cancer is not known. TAK-981 (subasumstat) is a small molecule inhibitor of the SUMO-activating enzyme (SAE) that forms a covalent adduct with an activated SUMO protein. Using T cells derived from patients with chronic lymphocytic leukemia (CLL), we demonstrate that targeting SAE activates type I interferon response. This is accompanied by largely intact T-cell activation in response to T-cell receptor engagement, with increased expression of CD69 and CD38. Furthermore, TAK-981 decreases Treg differentiation and enhances secretion of interferon-γ by CD4+ and CD8+ T-cells. These findings were recapitulated in mouse models, suggesting an evolutionarily conserved mechanism of T cell activation regulated by SUMO modification. Relevant to the consideration of TAK-981 as an effective agent for immunotherapy in hematological malignancies, we demonstrate that the downstream impact of TAK-981 administration is enhancement of the cytotoxic function of CD8+ T cells, thus uncovering immune implications of targeting sumoylation in lymphoid neoplasia.

The SUMOylation inhibitor TAK-981 (Subasumstat) triggers IFN-I-dependent activation of Natural Killer cells against Acute Myeloid Leukemias

“…Blockade of IFN-I receptor (IFNAR) indeed blunts the anti-tumoral immune response induced by TAK-981 in different immunocompetent mouse cancer models (10,12). Contrasting with these results, TAK-981dependent activation of T cells from Chronic Lymphocytic Leukemia patients was found independent of IFNAR signaling (14).…”

“…In addition to the overexpression of innate immunity activating ligands by cancer cells, recent studies have reported that inhibition of SUMOylation with TAK-981 activates an anti-tumor immune response and improves the efficiency of immune therapies by directly affecting immune cells. In models of pancreatic cancer and lymphomas, TAK-981 activates CD8 T-cells, NK cells, monocytes and dendritic cells (10)(11)(12)(13), and decreases regulatory T-cells (T-reg) differentiation (14). The immuno-modulatory function of TAK-981 was suggested to rely on its ability to induce type-I Interferon (IFN-I) secretion.…”

Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma

“…Preclinical studies have also demonstrated a role for TAK-981 in immune cells, changes that may promote cancer treatment benefit (Lam et al, 2023; Nakamura et al, 2022). This study did not evaluate a role of the immune system in SS, and further studies should be performed to elicit any additional effects TAK-981 may have in this context.…”

Positioning SUMO as an immunological facilitator of oncolytic viruses for high-grade glioma

“…The SUMO pathway is also implicated in the functioning of non-inhibitory effector T cells required for the development of antitumoral immunity. Lam et al (2023) reported enhanced secretion of IFNγ by CD4 + and CD8 + populations alongside enhanced T-cell-mediated cytotoxicity in OCI-LY3 lymphoma cultures after treatment with TAK-981. Other preclinical work has identified the specific role of various SUMO components in effector T-cell homeostasis and adaptations to the tumor microenvironment.…”