Rapid Depletion Of Intratumoral Regulatory T Cells Induces Synchronized Cd8 T- And Nk-Cell Activation And Ifn Gamma-Dependent Tumor Vessel Regression

Regulatory T cells (Tregs) are known to inhibit antitumor 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 tumorinfiltrating Tregs using anti-CD25-F(ab') 2 near-infrared photoimmunotherapy. Depletion of tumor-infiltrating Tregs induced transient but synchronized IFN gamma expression in CD8 T and natural killer (NK) cells. Despite the small fraction of CD8 T and NK cells contained within examined tumors, IFN gamma 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 gamma 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 Foxp3(DTR) mice; combination with IL15 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 gamma, providing insight into the mechanism of Treg-targeting therapies.Significance: Intratumoral Treg depletion induces synchronized intratumoral CD8 T- and NK-cell activation, IFN gamma-dependent tumor vessel regression, and ischemic tumor necrosis/apoptosis, indicating the roles of intratumoral Tregs to support the tumor vasculature.[GRAPHICS].