Antitumor effects of eribulin depend on modulation of the tumor microenvironment by vascular remodeling in mouse models

<jats:p>We previously reported that eribulin mesylate (eribulin), a tubulin‐binding drug (<jats:styled-content style="fixed-case">TBD</jats:styled-content>), could remodel tumor vasculature (i.e. increase tumor vessels and perfusion) in human breast cancer xenograft models. However, the role of this vascular remodeling in antitumor effects is not fully understood. Here, we investigated the effects of eribulin‐induced vascular remodeling on antitumor activities in multiple human cancer xenograft models. Microvessel densities (<jats:styled-content style="fixed-case">MVD</jats:styled-content>) were evaluated by immunohistochemistry (<jats:styled-content style="fixed-case">CD</jats:styled-content>31 staining), and antitumor effects were examined in 10 human cancer xenograft models. Eribulin significantly increased <jats:styled-content style="fixed-case">MVD</jats:styled-content> compared to the controls in six out of 10 models with a correlation between enhanced <jats:styled-content style="fixed-case">MVD</jats:styled-content> levels and antitumor effects (<jats:italic>R</jats:italic><jats:sup>2</jats:sup> = 0.54). Because of increased <jats:styled-content style="fixed-case">MVD</jats:styled-content>, we next used radiolabeled liposomes to examine whether eribulin treatment would result in increased tumoral accumulation levels of these macromolecules and, indeed, we found that eribulin, unlike vinorelbine (another <jats:styled-content style="fixed-case">TBD</jats:styled-content>) enhanced them. As eribulin increased accumulation of radiolabeled liposomes, we postulated that this treatment might enhance the antitumor effect of Doxil (a liposomal anticancer agent) and facilitate recruitment of immune cells into the tumor. As expected, eribulin enhanced antitumor activity of Doxil in a post‐erlotinib treatment H1650 (<jats:styled-content style="fixed-case">PE</jats:styled-content>‐H1650) xenograft model. Furthermore, infiltrating <jats:styled-content style="fixed-case">CD</jats:styled-content>11b‐positive immune cells were significantly increased in multiple eribulin‐treated xenografted tumors, and natural killer (<jats:styled-content style="fixed-case">NK</jats:styled-content>) cell depletion reduced the antitumor effects of eribulin. These findings suggest a contribution of the immune cells for antitumor activities of eribulin. Taken together, our results suggest that vascular remodeling induced by eribulin acts as a microenvironment modulator and, consequently, this alteration enhanced the antitumor effects of eribulin.</jats:p>