Abstract
BackgroundCD4+CD25+ regulatory T (Treg) cells suppress tumor immunity by inhibiting immune cells. Manipulation of Treg cells represents a new strategy for cancer treatment. Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, inhibits the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) on osteoblasts to inhibit osteoclastogenesis. In a mouse model of bisphosphonate-related osteonecrosis of the jaw, administration of ZA suppressed Treg-cell activity and activated inflammatory Th17 cells. However, the interaction between ZA and Treg cells remained unclear. This study investigated the immune modulation of Treg cells by ZA.MethodsFlow cytometry was used to analyze the phenotypic and immunosuppressive characteristics of Treg cells treated with ZA. Chemotactic migration was evaluated using transwell assays. Quantitative real-time PCR (qRT-PCR) was used to investigate the effect of ZA on the expression of suppressive molecules by Treg cells.ResultsProliferation of isolated Treg cells in culture was inhibited by ZA, although ZA did not induce apoptosis. qRT-PCR and flow cytometry showed that ZA significantly downregulated the expression of CCR4, CTLA4, PD-1 and RANKL on Treg cells. Chemotactic migration and immunosuppressive functions were also significantly attenuated in Treg cells pretreated with ZA, and these effects were dose-dependent. Co-culture with Treg cells significantly increased the migration rate of breast cancer cells, while pretreatment of Treg cells with ZA attenuated this effect.ConclusionsOur findings demonstrated that ZA acted as an immune modulator by significantly inhibiting the expansion, migration, immunosuppressive function and pro-metastatic ability of Treg cells. Immunomodulation of Treg cells by ZA represents a new strategy for cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-016-0183-7) contains supplementary material, which is available to authorized users.
Highlights
CD4+CD25+ regulatory T (Treg) cells suppress tumor immunity by inhibiting immune cells
Patients with early-stage breast cancer and multiple myeloma have been shown to benefit from the addition of Zoledronic acid (ZA) to adjuvant endocrine therapy, or to standard chemotherapy, respectively [20, 33]
We demonstrated that ZA influenced the suppressive activity of Regulatory T cells (Tregs) cells and significantly affected the ability of Treg cells to secrete receptor activator of nuclear factor kappa-B ligand (RANKL), which is known to promote breast cancer cell migration
Summary
CD4+CD25+ regulatory T (Treg) cells suppress tumor immunity by inhibiting immune cells. In a mouse model of bisphosphonate-related osteonecrosis of the jaw, administration of ZA suppressed Treg-cell activity and activated inflammatory Th17 cells. Infiltration of Treg cells into the tumor microenvironment was shown to promote tumor cell escape from immune surveillance, and contribute to tumor growth and progression, suggesting that Treg cells play an important role in the prognosis of cancer patients [3,4,5,6]. Zoledronic acid (ZA) is a third-generation nitrogencontaining bisphosphonate (BP) and is able to suppress osteoclastogenesis via the inhibition of RANKL expression on osteoblasts [12, 13]. Data from the Adjuvant Zoledronic acid to reduce recurrence (AZURE) trial suggested that ZA potentiated the activity of adjuvant endocrine therapy in postmenopausal patients [22]. A mouse model of ZA-related osteonecrosis of the jaw showed that ZA inhibited Treg-cell activity [23]. The aim of this study was to investigate how ZA affected tumor immunity via Treg cells
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