Abstract P5-05-03: Eribulin treatment activates type 1 IFNs to promote a gene expression signature associated with antitumor immunity

Immune checkpoint inhibitors targeting the PD1/PD-L1 and CTLA4 signaling axes have made a significant impact in the treatment of some solid tumors, particularly melanoma and non-small-cell lung carcinoma. While triple-negative breast cancers (TNBC) typically have poorer clinical outcomes due in part to a lack of targeted therapies, they are often more immunogenic than other types of breast cancer.1 Some forms of chemotherapy, including microtubule-targeting agents, have been proposed to enhance the efficacy of immunotherapy,2 which has resulted in the evaluations of combinations of these drugs in preclinical and clinical studies. Most notably, the combination of the PD-L1 inhibitor atezolizumab with the taxane nab-paclitaxel was shown to prolong progression-free survival in patients with metastatic TNBC.3 Although it is known that paclitaxel can function as a TLR4 agonist leading to activation of the innate immune system, there has been little comparison of the immunogenic effects elicited by different clinically used MTAs for the treatment of TNBC. We evaluated the effects of 5 distinct MTAs used for the treatment of TNBC, paclitaxel, docetaxel, ixabepilone, vinorelbine, and eribulin, on the expression of antitumor cytokines and other immunomodulatory genes in myeloid and in TNBC cells. Our results show that the expression signature generated by the microtubule stabilizers, paclitaxel, docetaxel, and ixabepilone, was markedly different from the signature elicited by the microtubule destabilizers eribulin and vinorelbine. The microtubule destabilizers caused upregulation of type 1 interferons and interferon-stimulated-genes (ISGs), effects not seen with the microtubule stabilizers. A time course analysis revealed that the transcriptional upregulation of the ISG CXCL10 by eribulin occurred before the expression of interferons. Mechanistically, microtubule destabilizer-induced expression of c-Jun which could upregulate the early expression of CXCL10 through activation of the AP-1 complex. The eribulin-mediated induction of type 1 interferons is similar to the expression signature promoted by the cGAS-STING pathway that has been shown to enhance the efficacy of checkpoint inhibitors,4 suggesting that microtubule destabilizers, but not stabilizers, can promote signaling through this pathway. Together, these results provide evidence that distinct MTAs have different immune modulatory properties and suggest that the specific immune signatures initiated by the different MTAs need to be considered for their optimal use with checkpoint inhibitors. These studies were funded by Eisai. 1. Liu, Z., Li, M., Jiang, Z. & Wang, X. A Comprehensive Immunologic Portrait of Triple-Negative Breast Cancer. Transl Oncol 11, 311-329, (2018). 2. Emens, L. A. & Middleton, G. The interplay of immunotherapy and chemotherapy: harnessing potential synergies. Cancer Immunol Res 3, 436-443, (2015). 3. Schmid, P. et al. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med 379, 2108-2121, (2018). 4. Cheng, N. et al. A nanoparticle-incorporated STING activator enhances antitumor immunity in PD-L1-insensitive models of triple-negative breast cancer. JCI Insight 3, (2018). Citation Format: Charles S Fermaintt, Shayne Hastings, Susan L Mooberry, April L Risinger. Eribulin treatment activates type 1 IFNs to promote a gene expression signature associated with antitumor immunity [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-05-03.