Research ArticleCancer Immunotherapy

CD25 Blockade Depletes and Selectively Reprograms Regulatory T Cells in Concert with Immunotherapy in Cancer Patients

Science Translational Medicine  16 May 2012:
Vol. 4, Issue 134, pp. 134ra62
DOI: 10.1126/scitranslmed.3003330

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Regulatory T cells (Tregs) are key mediators of immune tolerance and feature prominently in cancer. Depletion of CD25+ FoxP3+ Tregs in vivo may promote T cell cancer immunosurveillance, but no strategy to do so in humans while preserving immunity and preventing autoimmunity has been validated. We evaluated the Food and Drug Administration–approved CD25-blocking monoclonal antibody daclizumab with regard to human Treg survival and function. In vitro, daclizumab did not mediate antibody-dependent or complement-mediated cytotoxicity but rather resulted in the down-regulation of FoxP3 selectively among CD25high CD45RAneg Tregs. Moreover, daclizumab-treated CD45RAneg Tregs lost suppressive function and regained the ability to produce interferon-γ, consistent with reprogramming. To understand the impact of daclizumab on Tregs in vivo, we performed a clinical trial of daclizumab in combination with an experimental cancer vaccine in patients with metastatic breast cancer. Daclizumab administration led to a marked and prolonged decrease in Tregs in patients. Robust CD8 and CD4 T cell priming and boosting to all vaccine antigens were observed in the absence of autoimmunity. We conclude that CD25 blockade depletes and selectively reprograms Tregs in concert with active immune therapy in cancer patients. These results suggest a mechanism to target cancer-associated Tregs while avoiding autoimmunity.

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