Foxp3+ regulatory T cells suppress T cell immunity in inflamed and non-inflamed tumors by distinct mechanisms

Abstract

Abstract Foxp3+ regulatory T cells (Treg) are essential to prevent autoimmunity, but may also suppress anti-tumor immune responses. The relevance of Treg cell-mediated suppression in inflamed and non-inflamed (immune excluded or immune desert) tumors is not well understood. Here, we used Foxp3-DTR transgenic mice to selectively ablate Treg cells in mice with established tumors. We observed robust and rapid tumor clearance in a number of models, independent of the immune infiltration at baseline. These responses were driven by the induction of infiltration, proliferation, and cytokine production by CD8 T cells in tumor tissues. Importantly, pairing single cell TCR sequencing with transcriptome analysis revealed that CD8 T cells in the tumor acquired a progenitor exhausted phenotype and a clonally diverse TCR repertoire following Treg cell depletion. Pharmacological blockade of lymph node egress demonstrated that local Treg cell depletion and the resulting activation of tumor-infiltrating CD8 T cells was sufficient for tumor rejection in inflamed tumors. In contrast, short-term Treg cell depletion outside of the tumor and the resulting de novo generation of CD8 T cell responses facilitated the rejection of immune desert tumors. These data suggest that Treg cells play a critical role in suppressing both priming of novel anti-tumor CD8 T cell responses as well as limiting effector functionality of infiltrating CD8 T cells within the tumor microenvironment. More importantly, our data suggest that transient systemic Treg cell depletion can convert non-inflamed tumors into inflamed tumors.