Abstract P4-07-19: Eribulin enhances STING-dependent induction of type I interferons in immune and triple-negative breast cancer cells

Abstract

Triple-negative breast cancer (TNBC) is a heterogenous subtype of breast cancer that lacks effective targeted treatment options. However, TNBC typically has a higher mutational burden and greater degree of immunogenicity than other breast tumors, making immunotherapy a viable strategy for effective treatment of this disease. Strategies to improve the response of TNBC patients to immunotherapy include the upregulation of the cGAS-STING innate immune sensing pathway and STING agonists are in clinical development for the treatment of TNBC. We demonstrate that eribulin, a microtubule destabilizer currently used in the treatment of TNBC, functions as an indirect STING agonist because it promotes the release of mitochondrial DNA into the cytoplasm. Eribulin also enhances type I interferon expression induced by STING agonists through a second TBK1-dependent mechanism downstream of STING activation that is shared by the RIG/MAVS RNA sensing pathway. Both mechanisms of eribulin-mediated activation of interferon expression occur in immune and TNBC cells and are shared with other microtubule destabilizers, including vinorelbine, but not with the microtubule stabilizing agent paclitaxel. These effects of eribulin on innate immune sensing pathways in vitro prompted further evaluations of the impact of eribulin on the in vivo immunological response to mammary tumors. We found that eribulin, but not paclitaxel, promotes the activation of CD4+ T-cells in the spleens and draining lymph nodes of tumored animals. This activation required tumor priming but was independent of any direct effect on tumor growth inhibition, demonstrating a specific role of eribulin as a tumor immune modulator. These data contribute to accumulating evidence that there are important mechanistic differences between the microtubule targeted chemotherapeutics currently used in the treatment of TNBC and suggest that eribulin elicits a more favorable innate immunological signature than paclitaxel. Research supported by Eisai Inc. Citation Format: Leila Takahashi-Ruiz, Charles Fermaintt, Nancy Wilkinson, Susan Mooberry, April Risinger. Eribulin enhances STING-dependent induction of type I interferons in immune and triple-negative breast cancer cells [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-19.