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Cancer Therapy: Preclinical |
Authors' Affiliations: 1 Division of Neurosurgery, Department of Surgery and 2 Department of Pathology, Duke University Medical Center, Durham, North Carolina
Requests for reprints: John H. Sampson, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710. Phone: 919-684-9041; Fax: 919-684-9045; E-mail: john.sampson{at}duke.edu.
Purpose: Elevated proportions of regulatory T cells (Treg) are present in patients with a variety of cancers, including malignant glioma, yet recapitulative murine models are wanting. We therefore examined Tregs in mice bearing malignant glioma and evaluated anti-CD25 as an immunotherapeutic adjunct.
Experimental Design: CD4+CD25+Foxp3+GITR+ Tregs 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 Tregs, 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+ Tregs 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 Tregs, reducing their number only moderately, yet eliminating their suppressive function. This elimination of Treg function permits enhanced lymphocyte proliferative and IFN-
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 Tregs but does prevent Treg function. This leads to safe enhancement of tumor immunity in a murine glioma model that recapitulates the tumor-induced changes to the CD4 and Treg compartments seen in patients with malignant glioma.
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