Acquisition of suppressive function by conventional T cells limits antitumor immunity upon T_reg depletion

Regulatory T (T-reg) cells contribute to immune homeostasis but suppress immune responses to cancer. Strategies to disrupt T-reg cell-mediated cancer immunosuppression have been met with limited clinical success, but the underlying mechanisms for treatment failure are poorly understood. By modeling T-reg cell-targeted immunotherapy in mice, we find that CD4(+) Foxp3(-) conventional T (T-conv) cells acquire suppressive function upon depletion of Foxp3(+) T-reg cells, limiting therapeutic efficacy. Foxp3(-) T-conv cells within tumors adopt a T-reg cell-like transcriptional profile upon ablation of T-reg cells and acquire the ability to suppress T cell activation and proliferation ex vivo. Suppressive activity is enriched among CD4(+) T-conv cells marked by expression of C-C motif receptor 8 (CCR8), which are found in mouse and human tumors. Upon T-reg cell depletion, CCR8(+) T-conv cells undergo systemic and intratumoral activation and expansion, and mediate IL-10-dependent suppression of antitumor immunity. Consequently, conditional deletion of Il10 within T cells augments antitumor immunity upon T-reg cell depletion in mice, and antibody blockade of IL-10 signaling synergizes with T-reg cell depletion to overcome treatment resistance. These findings reveal a secondary layer of immunosuppression by T-conv cells released upon therapeutic T-reg cell depletion and suggest that broader consideration of suppressive function within the T cell lineage is required for development of effective T-reg cell-targeted therapies.