IL-6R blockade with tocilizumab disrupts pericyte- and tumor cell-driven IL-6/STAT3 signaling, enhancing docetaxel efficacy in ER+ breast cancer.

Metastatic breast cancer is a global health concern with a persistently low five-year survival rate. Taxane microtubule stabilizers, including docetaxel (DTX), are the standard of care in various treatment protocols. DTX is used both as a single agent and in combination therapies, with a majority of ER+ breast cancer patients ultimately developing chemoresistance. The mechanisms contributing to chemoresistance involving the tumor microenvironment (TME) have not been fully elucidated. Specifically, the role of vascular cells within the TME, particularly pericytes, is understudied, and their role in promoting chemoresistance remains unknown. Inflammatory cytokines such as interleukin 6 (IL-6) are known to drive drug resistance via activation of the pro-survival JAK/STAT pathway. We found that DTX induced IL-6 secretion of pericytes by at least two-fold compared to vehicle-treated controls in vitro. All tested breast cancer cell lines expressed subunits of the IL-6 receptor (IL-6R) complex, indicating their capacity to respond to JAK/STAT signaling. Conditioned media from DTX-treated pericytes activated STAT3 in ER+ breast cancer cells to levels comparable to recombinant IL-6. Pharmacologic blockade of IL-6 signaling with the IL-6R inhibitor, tocilizumab, reduced DTX-induced STAT3 activation in vitro. Furthermore, combined treatment with tocilizumab and DTX synergistically suppressed the growth of zero-passage patient-derived ER+ breast cancer organoids expressing intact IL-6 signaling. Together, our findings suggest that combining DTX with tocilizumab may revert DTX-induced chemoresistance in ER+ breast cancer patients by inhibiting IL-6-mediated activation of the STAT3 pathway.