Abstract 6397: Eribulin acts as an immune adjuvant to enhance the antitumor efficacy of STING agonists in triple-negative breast cancer models
Authors: Takahashi-Ruiz Leila , Fermaintt Charles S. , Wilkinson Nancy , Chan Peter Y. , Mooberry Susan L. , Risinger April L. 
Published: April 2023

Triple-negative breast cancer (TNBC) is a heterogenous subtype of breast cancer lacking 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. 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. We previously showed that eribulin, a microtubule destabilizer used in the treatment of TNBC, functions as an indirect STING agonist because it promotes the release of mitochondrial DNA into the cytoplasm. In separate studies, we demonstrated that eribulin also significantly enhances type I interferon expression induced by STING agonists through a second TBK1-dependent mechanism downstream of STING activation. Both mechanisms of eribulin-mediated activation of interferon expression occur in immune and TNBC cells and are shared with other microtubule destabilizers but not with the microtubule stabilizer paclitaxel. Our current studies demonstrate the in vivo immunological effects of the microtubule destabilizer eribulin with the STING agonist ADU-S100 that lead to a significant decrease in tumor growth in the spontaneous MMTV-PyVT mammary tumor model upon combination treatment. The immunostimulatory effects of eribulin with or without concurrent administration of a STING agonist were determined in the spleen, tumor draining lymph nodes, and tumors with distinct effects observed in the activation of innate and adaptive responses. We further demonstrate the immunological and antitumor efficacy of combinations of eribulin and ADU-S100 in the syngeneic 4T1 model that is resistant to the antimitotic effects of eribulin as a single agent. Even in the absence of direct antimitotic effects on the tumor, eribulin was sufficient to promote activation of CD4+CD25− effector T-cells in the spleen and lymph nodes specifically in tumored animals but not untumored controls. Additionally, eribulin was able to promote a similar increase in the activation of CD4+ effector T-cells even in untumored animals when administered in combination with a STING agonist. Together, these data contribute to accumulating evidence that there are important mechanistic differences between the microtubule targeted chemotherapeutics currently used in the treatment of TNBC that could inform on their more rational use in the clinic as single agents or as chemotherapeutic backbones in combination with targeted therapy, including immunotherapeutics. More specifically, our data demonstrate that eribulin can act as an immune adjuvant to promote STING signaling and T-cell activation in multiple in vivo TNBC models in addition to its well established anti-mitotic effects to enhance antitumor efficacy.

Citation Format: Leila Takahashi-Ruiz, Charles S. Fermaintt, Nancy Wilkinson, Peter Y. Chan, Susan L. Mooberry, April L. Risinger. Eribulin acts as an immune adjuvant to enhance the antitumor efficacy of STING agonists in triple-negative breast cancer models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6397.