Targeted ablation of FoxP3+ T cells activates peripheral and tumor-infiltrating cytotoxic CD8+ T cells in multiple syngeneic mouse tumor models

Abstract

Abstract FoxP3+ regulatory T cells (Treg) are essential to prevent autoimmunity, but have also been implicated in suppressing anti-tumor immune responses. We assessed the impact of Treg depletion in 8 different syngeneic tumor models, including cancer immunotherapy-sensitive and -resistant models. Robust, rapid tumor control or regression was observed in all models tested. Analysis of both peripheral and tumor-infiltrating T cells revealed that Treg depletion resulted in robust proliferation and cytokine production by CD8+ T cells in lymph nodes, spleen, and tumor tissue. Tumor regression was CD8+ T cell-dependent, as antibody mediated-depletion of these cells abrogated tumor regression in a representative model. Interestingly, studies using FTY720 to pharmacologically block T cell egress from the lymph nodes suggest that following Treg depletion, cancer immunotherapy-sensitive models may not require new T cell infiltration into the tumor for tumor regression. This is in contrast to an immunotherapy-resistant model, which failed to regress following Treg depletion when lymph node egress was concurrently blocked. These data suggest that Tregs play a critical role in suppressing both priming of novel anti-tumor CD8+ T cells responses as well as limiting effector functionality of tumor-infiltrating CD8+ T cells within the tumor microenvironment.