Systemic Anti-CD25 Monoclonal Antibody Administration Safely Enhances Immunity in Murine Glioma without Eliminating Regulatory T Cells

Abstract

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 examinedT regs in mice bearing malignant glioma and evaluated anti-CD25 as an immunotherapeutic adjunct. + 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-g 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 eliminateT 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.

In vivo depletion of CD4+FOXP3+ Treg cells by the PC61 anti‐CD25 monoclonal antibody is mediated by FcγRIII+ phagocytes

“…1 also [17]). In contrast to the original hypothesis, our data and several others [15,[17][18][19][20][21] have shown that PC61 mAb treatment does not completely remove Foxp3 1 Treg. In peripheral blood, $30% of Foxp3 1 Treg with low or no CD25 expression remain untouched by PC61 mAb (Fig.…”

Glioma Cells Display Complex Cell Surface Topographies That Resist the Actions of Cytolytic Effector Lymphocytes

“…CTLs fail to generate an effective immune response to the GBM, as evidenced by improved survival. Immunosuppressive cytokines, inhibitory factors, monocyte-derived suppressor cells, T regulatory cells, and other factors limit the immune response via multiple mechanisms that inhibit dendritic cell (DC) maturation, Ag presentation, and T cell activation (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Therefore, any successful immunotherapeutic approach to GBM must overcome the challenges of access to the tumor, poor immunogenicity of the tumor, and the immunosuppressive effect of GBMderived cytokines.…”

Dendritic cells based immunotherapy of patient with chondrosarcoma--case report.

“…CD4+/CD25+/FOXP3+ Treg cells are well known as immunosuppressive agents hampering anti-tumor response and elimination of these cells enhances immunity and effectiveness of DCs vaccinations [19,20]. Failure in the maintenance of CD4+/CD25+/FOXP3+ Treg lymphocytes on the low level could be one of the reason of ineffectiveness of vaccination and lack of both clinical and immune response.…”