Systemic anti-CD25 monoclonal antibody administration safely enhances immunity in murine glioma without eliminating regulatory T cells

Purpose: Elevated proportions of regulatory T cells (T-reg) are present in patients with a variety of cancers, including malignant glioma, yet recapitulative murine models are wanting. We therefore examined T-regs in mice bearing malignant glioma an devaluated anti-CD25 as an immunotherapeutic adjuncts. Experimental Design: CD4(+)CD25(+)Foxp3(+)GITR(+) T-regs were quantified in the peripheral blood, spleens, cervical lymph nodes, and bone marrow of mice bearing malignant glioma. The capacities for systemic anti-CD25 therapy to deplete T-regs, enhance lymphocyte function, and generate antiglioma CTL responses were assessed. Lastly, survival and experimental allergic encephalitis risks were evaluated when anti-CD25 was combined with a dendritic cell - based immunization targeting shared tumor and central nervous system antigens. Results: Similar to patients with malignant glioma, glioma-bearing mice show a CD4 lymphopenia. Additionally, CD4(+)CD25(+)Foxp3(+)GITR(+) T-regs represent an increased fraction of the remaining peripheral blood CD4(+) T cells, despite themselves being reduced in number. Similar trends are observed in cervical lymph node and spleen, but not in bone marrow. Systemic anti-CD25 administration hinders detection of CD25(+) cells but fails to completely eliminate T-regs, reducing their number only moderately, yet eliminating their suppressive function. This elimination of T-reg function permits enhanced lymphocyte proliferative and IFN-gamma responses and up to 80% specific lysis of glioma cell targets in vitro. When combined with dendritic cell immunization, anti-CD25 elicits tumor rejection in 100% of challenged mice without precipitating experimental allergic encephalitis. Conclusions: Systemic anti-CD25 administration does not entirely eliminate T-regs, but does prevent T-reg function. This leads to safe enhancement of tumor immunity in a murine glioma model that recapitulates the tumor-induced changes to the CD4 and T-reg compartments seen in patients with malignant glioma.