Abstract PS17-18: Eribulin-mediated release of mitochondrial DNA activates the cGAS-STING innate immune signaling pathway
Authors: Charles Steven Fermaintt, Leila Takahashi-Ruiz, Susan L Mooberry, April L Risinger
Journal: Cancer Research (2021)

Abstract Triple-negative breast cancer (TNBC) patients have a higher response rate to immune checkpoint inhibitors as compared to patients with other types of breast cancer. This higher response rate is thought to be due to higher mutational burdens, the prevalence of PD-L1/PD-1 expression, and immune cell infiltration in TNBC. However, less than half of TNBC patients respond to these drugs as single agents, which has prompted their use in combination with chemotherapy, including microtubule targeted agents (MTAs). Multiple clinical trials now show that the combination of PD-1/PD-L1-targeted immune checkpoint inhibitors with chemotherapy, including the MTAs paclitaxel or eribulin, can improve clinical responses in both late and early-stage TNBC. Previous studies have demonstrated that MTAs can activate innate immune sensing pathways that could potentially mediate their efficacy in combination with immunotherapies, including the ability of paclitaxel to promote TLR4 signaling. However, there has not been a direct comparison of the immunogenic effects elicited by each of the five MTAs that are used to treat TNBC to inform on how agents of this class could differentially alter the tumor immune microenvironment. In the current study, we determined the concentration and time-dependent effects of paclitaxel, docetaxel, ixabepilone, eribulin, and vinorelbine on the cytokine expression profiles in both immune and TNBC cells. Our results demonstrate that the microtubule destabilizers, eribulin, and vinorelbine, but not the microtubule stabilizers, paclitaxel, docetaxel, and ixabepilone, promote upregulation of type 1 interferons (IFNα/β) and downstream interferon-stimulated-genes. A time-course analysis in the human monocytic THP-1 cell line and primary murine bone-derived macrophages found that the induction of IFNβ by eribulin occurred within 2-6 hours and was independent of mitotic arrest. A pharmacological and genetic-based assessment of the signaling pathways responsible for the eribulin-mediated expression of IFNβ revealed a dependency on the cGAS-STING cytosolic DNA-sensing innate immune signaling pathway in both immune and TNBC cells. Moreover, we demonstrate that the mechanism for the promotion of cGAS-STING-dependent interferon induction by eribulin is due to the release of mitochondrial DNA (mtDNA) into the cytoplasm. Together, these results provide evidence that different MTAs have distinct immunomodulatory properties and highlight the ability of eribulin to promote the release of mtDNA to activate the cGAS-STING pathway, which has been previously shown to enhance the efficacy of immunotherapy in TNBC. These studies were funded by Eisai. Citation Format: Charles Steven Fermaintt, Leila Takahashi-Ruiz, Susan L Mooberry, April L Risinger. Eribulin-mediated release of mitochondrial DNA activates the cGAS-STING innate immune signaling pathway [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-18.