Zoledronic acid induces an immune response through increased central memory and effector memory gamma/delta T cells in early and metastatic breast cancer patients

Abstract

Introduction: Zoledronic acid (ZA) in combination with endocrine therapy (ET) and ovarian ablation yielded a disease-free survival and overall survival advantage in women with estrogen receptor+ early stage breast cancer (EBC). Evidence from preclinical studies suggests that ZA increases gamma/delta T cells (GDT). Materials and Methods: We examined immune responses following ZA in 24 BC patients by collecting peripheral blood mononuclear cells at day 0, 1, 7, and 28. GDT population and cytokine responses were assayed using flow cytometry and multi-analyte profiling beads (Luminex), respectively, and relative changes from baseline were analyzed using the Wilcoxon signed-rank test. Results: In total, 18 (75%) patients had metastatic breast cancer (MBC), 6 (25%) had EBC, 18 (75%) received ET, 4 (17%) chemotherapy (C), and 2 (8%) no concurrent therapy. Following ZA, an increase in both effector (CD3+/Vdelta2+/CD45RA−/CD27−) ( P = 0.0005) and central memory GDT (CD3+/Vdelta2+/CD45RA−/CD27+) ( P = 0.006), as well as a decrease in naive GDT (CD3+/Vdelta2+/CD45RA+/CD27+) ( P = 0.003) were observed at day 7. Cytokines, including interleukin-1 (IL-1) receptor antagonist ( P P P P P Conclusion: In both EBC and MBC patients, ZA appears to induce a significant change in GDTs and cytokines associated with cell-mediated immunity offering a possible biologic mechanism for ZA's anticancer activity. Further studies are necessary to determine which BC patients might achieve clinically meaningful anticancer benefits from ZA.