PT - JOURNAL ARTICLE AU - Ping Li AU - Fengyang Chen AU - Jingbin Zheng AU - Yang Yang AU - Yuan Li AU - Yifei Wang AU - Xin Chen TI - Cyclophosphamide abrogates the expansion of CD4<sup>+</sup>Foxp3<sup>+</sup> regulatory T cells and enhances the efficacy of bleomycin in the treatment of mouse B16-F10 melanomas AID - 10.20892/j.issn.2095-3941.2021.0027 DP - 2021 Nov 01 TA - Cancer Biology &amp; Medicine PG - 1010--1020 VI - 18 IP - 4 4099 - http://www.cancerbiomed.org/content/18/4/1010.short 4100 - http://www.cancerbiomed.org/content/18/4/1010.full SO - Cancer Biol Med2021 Nov 01; 18 AB - Objective: Promotion of the proliferative expansion of CD4+Foxp3+ regulatory T cells (Tregs) is one of the side effects that limits the use of bleomycin (BLM) in the treatment of tumors. In this study, we examined the hypothesis that cyclophosphamide (CY), a chemotherapeutic agent with the capacity to eliminate tumor infiltrating Tregs, abrogated BLM-induced expansion of Tregs and consequently resulted in a better anti-tumor effect.Methods: The in vitro effects of BLM, with or without mafosfamide (MAF, the active metabolite of CY), on both TGF-β-induced differentiation of Tregs (iTregs), and TNF-induced expansion of naturally occurring Tregs (nTregs) were assessed. The in vivo effect of low doses of BLM and CY on tumor-infiltrating Tregs, as well as on the growth of mouse B16-F10 melanomas, was also studied.Results: In vitro treatment with BLM promoted the differentiation of iTregs, as well as TNF-induced expansion of nTregs. These effects of BLM were completely abrogated by MAF. Furthermore, in the mouse B16-F10 melanoma model, treatment with low doses of BLM increased the number of tumor-infiltrating Tregs, and this effect of BLM was also abrogated by CY. Importantly, combination therapy with low doses of BLM and CY showed synergistic anti-tumor effects.Conclusions: CY abrogated the effect of BLM on the expansion of Tregs. The combination of these 2 chemotherapeutic agents may represent a safer and more effective therapy in the treatment of cancer patients, and thus merits future clinical evaluation.