Abstract
Abstract CD4+FoxP3+ regulatory T cells (Tregs) accumulate at tumor sites and within the peripheral blood of patients with a variety of cancers. Tregs suppress antigen-specific immune responses, and represent a major barrier to the efficacy of cancer immunotherapy. We previously conducted a dose-ranging study of low dose Cyclophosphamide (0, 200, 250, and 350 mg/m2) given one day prior to a granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting HER-2+ breast cancer vaccine in 28 patients with metastatic breast cancer. We found that vaccine-induced HER-2-specific immunity was best optimized by 200 mg/m2 CY, and that doses of CY higher than 200 mg/m2 suppressed antigen-specific immunity. To further explore the pharmacodynamic impact of CY on immune priming, we analyzed Tregs and effector CD4+ T cells present in peripheral blood mononuclear cells (PBMC) collected pre- and post-vaccination with or without CY by flow cytometry. We found that the percentage of CD4+FoxP3+ Tregs in PBMC did not change with vaccination alone. Conversely, CY at doses of either 200 or 250 mg/m2 selectively induced the apoptosis of CD4+FoxP3+ Tregs relative to CD4+FoxP3− effector T cells, and CY at 350 mg/m2 induced apoptosis of both CD4+FoxP3+ Tregs and CD4+FoxP3− effector T cells. Finally, CY at all doses selectively decreased CCR7−CD45RA− effector memory Tregs and increased CCR7+CD45RA+ naïve Tregs relative to vaccine alone. Collectively, these data suggest that low dose CY selectively induces apoptosis of CD4+FoxP3+ Tregs relative to CD4+FoxP3− effector T cells, providing a window for more efficient induction of vaccine-induced HER-2-specific immunity. Citation Format: Gang Chen, James M. Leatherman, Melek Erdinc Sunay, Leisha A. Emens. Cyclophosphamide induces dose dependent apoptosis of CD4+FoxP3+ regulatory T cells relative to CD4+FoxP3- effector T cells in breast cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4749. doi:10.1158/1538-7445.AM2013-4749
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