Multiple Low Doses of 5-Fluorouracil Diminishes Immunosuppression by Myeloid Derived Suppressor Cells in Murine Melanoma Model

Abstract

Background: Melanoma progression and metastasis is suggested to be mediated by increased accumulation of myeloid derived suppressor cells. Various chemotherapeutic drugs such as 5-Fluorouracil in single low concentration have the capacity, at least in part, to reverse tumor progression by reducing myeloid derived suppressor cells-mediated immunosuppression. Objective: To assess whether multiple low doses of 5-fluorouracil could repress myeloid derived suppressor cells in low frequency and, in turn, could enhance anti-tumor responses and promote a more prolonged survival in a murine melanoma model. Methods: Fifty milligram per kilogram body weight dose of 5-Flourouracil was administered intraperitoneally 4 times with 3-day intervals to C57BL/6 mice after B16 melanoma tumor models were established. The frequency and suppressive functions of myeloid derived suppressor cells and induction of anti-tumor CD8(+) T cells as well as tumor growth and survival were evaluated in drug treated and untreated mice. Results: Our results demonstrated that this therapeutic strategy increases the overall mice survival (p <= 0.01) and induces melanoma-specific CD8(+) T cell immunity (p <= 0.01) by reducing the frequency of myeloid derived suppressor cells (p <= 0.01) as well as their immune suppressive functions (p <= 0.05). Conclusion: Altogether, our data suggest that 5-fluorouracil in multiple low regimens might be used to overcome tumor immunosuppression and improve the efficacy and outcome of antitumor immune responses in a mouse model.