TAK-981 is a novel and selective small molecule inhibitor of the small ubiquitin-like modifier (SUMO) ylation enzymatic cascade in Phase 1 clinical trials. SUMOylation is a reversible post-translational modification that regulates protein function by covalent attachment of a SUMO protein to protein substrates. We have found that in vivo inhibition with TAK-981 promotes an antitumor immune response characterized by induction of a Type I interferon (IFN) response in immune cells. Interestingly, others have also reported a role for SUMOylation in restraining Type I IFN responses, upon exposure to pathogenic stimuli, using genetic approaches to inhibit SUMOylation. In this study, we demonstrate that inhibition of SUMOylation with TAK-981 enhances antitumor innate immunity by modulating macrophage and NK cell function. In vitro studies revealed that TAK-981 treatment increased expression of pro-inflammatory markers and prevented expression of anti-inflammatory markers on macrophages. TAK-981 treatment of macrophages further resulted in potent phagocytic activity against cancer cells. TAK-981 also induced expression of activation markers on NK cells and enhanced cell killing activity against cancer cells. Enhancement of macrophage phagocytosis and NK cell cytotoxicity by TAK-981 were shown to be dependent on Type I IFN receptor signaling, and both activities against CD20-positive cancer cells were further enhanced in the presence of the anti-CD20 therapeutic monoclonal antibody rituximab. Evaluation of combination activity in vivo in CD20-positive lymphoma xenograft models demonstrated synergistic antitumor activity in multiple models when TAK-981 was combined with rituximab. Inhibiting SUMOylation with TAK-981 appears to represent a novel and mechanistically unique means to the end of leveraging the potential of Type I IFNs to promote antitumor immune responses.
Citation Format: Akito Nakamura, Stephen Grossman, Keli Song, Neeraja Idamakanti, Gary Shapiro, Dennis Huszar. Inhibition of SUMOylation by TAK-981 induces antitumor innate immune responses by modulating macrophage and NK cell function through Type I IFN pathway activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1523.