Regulatory T cell depletion promotes myeloid cell activation and glioblastoma response to anti-PD1 and tumor-targeting antibodies

Glioblastoma is invariably lethal and responds poorly to immune checkpoint blockade. Here, we examined the impact of regulatory T (Treg) cell depletion on glioblastoma progression and immunotherapy responsiveness. In human glioblastoma, elevated Treg cell signatures correlated with poorer survival outcomes, with these cells expressing high levels of CD25. In Nf1^-/-Pten^-/-EGFRvIII⁺ glioblastoma-bearing mice, a single dose of non-interleukin-2 (IL-2) blocking (NIB) anti-CD25 (anti-CD25^NIB) antibody depleted Treg cells and promoted CD8⁺ T cell clonal expansion and partial tumor control, further enhanced by programmed cell death-1 (PD1)-blockade. Treg cell depletion induced interferon-γ (IFN-γ)-dependent tumor microenvironment remodeling, increasing Fcγ receptor (FcγR) expression on intratumoral myeloid cells and enhancing phagocytosis. Combination of anti-CD25^NIB with anti-EGFRvIII tumor-targeting antibodies resulted in complete tumor control. Anti-human CD25^NIB treatment of glioblastoma patient-derived tumor fragments effectively depleted Treg cells and activated CD8⁺ T cells. These findings underscore the therapeutic relevance of Treg targeting in glioblastoma and unveil potent combination strategies for anti-CD25^NIB based on innate cell activation.