Abstract 5522: Evaluation of eribulin-induced alterations of the intact immune cell landscape in spleens and tumors from tumor-bearing immunocompetent mice
Authors: Wu Haochen , Zhu Keyi , Tu Xiaolong , Albu Diana , Woodall-Jappe Mary , Littlefield Bruce A. 
Published: September 2020

Abstract
Eribulin, a synthetic analog of the marine sponge natural product halichondrin B, is approved in the US for certain patients with advanced breast cancer or liposarcoma. Its mechanisms of action include both cytotoxic, antimitotic effects as well as non-cytotoxic effects on tumor vasculature, phenotype and microenvironment. Known aspects of eribulin's effects on tumor phenotype, including reversal of epithelial-mesenchymal transition (EMT) and induction of cellular differentiation in various preclinical models, led us to speculate that eribulin might also alter immune homeostasis in the in vivo setting, both in tumors themselves as well as supporting immune organs such as the spleen. Here, we report on eribulin's effects on both lymphoid and myeloid lineage cellular components in both spleen and tumors from immunocompetent mice bearing subcutaneous Lewis lung carcinoma (LLC) isografts. Surprisingly, spleens of vehicle treated, LLC tumor-bearing mice are approximately twice as large spleens from non-tumor-bearing mice, with an excellent correlation (r2 = 0.92) between individual tumor size and spleen weight arguing for a direct cause and effect relationship between the presence of tumor and splenomegaly. Tumor-induced splenomegaly is associated with increased proliferation of splenic non-lymphoid (CD4-/CD8-/CD19-) cells, including both CD11b+ mature myeloid lineage cells as well as CD11b- cells. Due to high levels of P-glycoprotein (PgP) characteristic of most murine tumors, LLC tumors respond poorly to eribulin, a known PgP substrate. Thus, 3 doses of MTD eribulin (1.6 mg/kg; Q4Dx3) led to only a 30% reduction in tumor volume relative to vehicle-treated mice. Unexpectedly, however, despite this reduced tumor volume, spleens from eribulin-treated mice were twice again larger than the already-enlarged spleens from vehicle-treated tumor-bearing mice, and the clear relationship between tumor size and spleen weight was abolished. This additional eribulin-induced splenomegaly was associated with enhanced proliferation of the same CD4-/CD8-/CD19- non-lymphoid cells, CD11b+ myeloid lineage cells and CD11b- cells as in vehicle-treated, tumor-bearing mice. Evaluation of immune cell components in the associated fixed tumors from eribulin- and vehicle-treated mice is currently ongoing to assess what effect, if any, such changes in the spleen will have on the tumor immune microenvironment; these results will be presented at the meeting. In conclusion, our results point to significant and unexpected effects of eribulin treatment on the immune cell landscape in spleens and tumors from tumor-bearing immunocompetent mice.
Citation Format: Haochen Wu, Keyi Zhu, Xiaolong Tu, Diana Albu, Mary Woodall-Jappe, Bruce A. Littlefield. Evaluation of eribulin-induced alterations of the intact immune cell landscape in spleens and tumors from tumor-bearing immunocompetent mice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5522.