Rapid Depletion of Intratumoral Regulatory T cells Induces Synchronized CD8 T and NK Cell Activation and IFN-γ-dependent Tumor Vessel Regression.

Regulatory T cells (Tregs) are known to inhibit anti-tumor immunity, yet the specific mechanism by which intratumoral Tregs promote tumor growth remains unclear. To better understand the roles of intratumoral Tregs, we selectively depleted tumor-infiltrating Tregs using anti-CD25-F(ab')2 near-infrared photoimmunotherapy (NIR-PIT). Depletion of tumor-infiltrating Tregs induced transient but synchronized IFN-γ expression in CD8 T and natural killer (NK) cells. Despite the small fraction of CD8 T and NK cells contained within examined tumors, IFN-γ produced by these CD8 T and NK cells led to efficient and rapid tumor vessel regression, intratumoral ischemia, and tumor necrosis/apoptosis and growth suppression. IFN-γ receptor expression on vascular endothelial cells was required for these effects. Similar findings were observed in the early phase of systemic Treg depletion in tumor-bearing Foxp3DTR mice; combination with IL-15 therapy further inhibited tumor growth and achieved increased complete regression. These results indicate the pivotal roles of intratumoral Tregs in maintaining tumor vessels and tumor growth by suppressing CD8 T and NK cells from producing IFN-γ providing insight into the mechanism of Treg-targeting therapies.