Estrogen modulates NK and CD8 + T cell response via the PD-1 PD-L1 axis impairing antitumour effects of zoledronic acid

Clinical trials in breast cancer have demonstrated reduced recurrence in bone and soft tissue in postmenopausal women following either neoadjuvant or adjuvant treatment with Zoledronic acid (Zol). In contrast however, the same treatment resulted in an increased risk of extra-skeletal recurrence in premenopausal women. The reason for these stark differences has remained unclear, until now, preventing thousands of young breast cancer patients from being able to benefit from the life prolonging effects of Zol. Here we demonstrate that Zol induces an anti-tumor response by increasing infiltration of CD8 + T, dendritic and NK cells into soft tissue metastases, but only when estrogen concentrations are low. Anti-tumor response to Zol appears to be CD8 + T and NK cell-dependent in soft tissue, but only NK cell-dependent in bone. Conversely, elevated levels of estrogen are associated with reduced systemic and tumor infiltrating CD8+ and CD4 + T cells, increased PD-1 expression on T and NK cells, and PD-L1 on tumor cells. We propose that premenopausal concentrations of estradiol antagonize Zol-induced anti-tumor immunity, which relies on CD8 + T-cells and NK cells—an effect that is reversed by PD-1/PD-L1 blockade.